high-throughput-analysis-mammalian-olfactory-receptors-measurement

High-throughput Analysis of Mammalian Olfactory Receptors: Measurement of Receptor Activation via Luciferase Activity

Odorants create unique and overlapping patterns of olfactory receptor activation, allowing a family of approximately 1,000 murine and 400 human receptors ...

Monell Chemical Senses Center

Olfactory plasticity: one nostril knows what the other learns.

Sniffs are modulated in response to odor content. Higher concentrations of odor induce lesser-volume sniffs. This phenomenon implicates a neural feedback mechanism that measures sensory input (odor concentration) and modulates motor output (sniffing) accordingly. Here we used air-dilution olfactometry to probe the time course of this olfactomotor mechanism. A stainless-steel computer-controlled olfactometer, equipped with mass flow controllers, temperature and humidity control, and on-line photo-ionization detection, was coupled to a highly sensitive pneumatotachograph that measured nasal flow. The olfactometer was used to generate four ascending concentrations of the odorants propionic acid and phenethyl alcohol. Sniff volume was inversely related to odor concentration (P > 0.0001). Sniffs were uniform and concentration independent for the initial 150 ms but acquired a concentration-dependent flowrate as early as 160 ms following sniff onset for propionic acid (P > 0.05) and 260 ms for phenethyl alcohol (P > 0.05). Considering that odorant transduction takes around 150 ms and odorant-induced cortical evoked potentials have latencies of around 300 ms, the rapid motor adjustments measured here suggest that olfactomotor sniff feedback control is subcortical and may rely on neural mechanisms similar to those that modulate eye movements to accommodate vision and ear movements to accommodate audition.

Rapid olfactory processing implicates subcortical control of an olfactomotor system.

It has been estimated that approximately 30% of the population is unable to detect the odor of androstenone. These estimates, however, were made using tests and criteria optimized for identifying detection. Such criteria favor Type II over Type I errors--that is, they are excellent at identifying true detectors at the cost of erroneously labeling some detectors as non-detectors. Because these criteria were used to identify non-detectors, it is possible that the rate of non-detection may have been overestimated. To test this we screened 55 subjects for non-detection employing previously used methods. This screen yielded nine putative non-detectors, a 16.3% putative non-detection rate. We then retested these putative non-detectors using a forced choice (yes-no) paradigm to obtain a precise measure of their sensitivity. We found that this group of putative non-detectors was significantly above chance at detecting androstenone (P < 0.001), despite very low self-confidence in their performance. Based on the results of the signal detection analysis in this sample, we estimate the rate of actual androstenone non-detection in young healthy adults is between 1.8 and 5.96%, which is significantly lower than previously estimated. This finding is significant considering the implications of specific anosmias on the understanding of odor discrimination.

The prevalence of androstenone anosmia.

Functional imaging studies of olfaction have consistently reported odorant-induced activation of the cerebellum. However, the cerebellar role in olfaction remains unknown. We examined the olfactory and olfactomotor abilities of patients with unilateral cerebellar lesions, comparing performance within subjects across nostrils, as well as between subjects with age-matched and young controls. Regarding olfactory performance, initial testing revealed that patients had a contralesional impairment in olfactory identification but not olfactory detection threshold. However, when tested under conditions that prevented compensatory sniffing strategies, the patients also exhibited a contralesional olfactory detection impairment. Regarding olfactomotor function, a healthy olfactomotor system generates sniffs that are (1) sufficiently vigorous and (2) inversely proportional to odorant concentration in sniff mean airflow velocity, maximum airflow velocity, volume, and duration. Patients' sniffs were lower in overall airflow velocity and volume in comparison with control participants. Furthermore, reduced sniff velocity predicted poorer detection thresholds in patients. Finally, whereas young controls used concentration-dependent sniffs, there was a trend in that direction only for age-matched controls. Patients used sniffs that were concentration invariant. In conclusion, cerebellar lesions impacted olfactory and olfactomotor performance. These findings strongly implicate an olfactocerebellar pathway prominent in odor identification and detection that functionally connects each nostril primarily to the contralateral cerebellum.

Olfactory impairments in patients with unilateral cerebellar lesions are selective to inputs from the contralesional nostril.

Deciphering olfactory encoding requires a thorough description of the ligands that activate each odorant receptor (OR). In mammalian systems, however, ligands are known for fewer than 50 of more than 1400 human and mouse ORs, greatly limiting our understanding of olfactory coding. We performed high-throughput screening of 93 odorants against 464 ORs expressed in heterologous cells and identified agonists for 52 mouse and 10 human ORs. We used the resulting interaction profiles to develop a predictive model relating physicochemical odorant properties, OR sequences, and their interactions. Our results provide a basis for translating odorants into receptor neuron responses and for unraveling mammalian odor coding.

Odor coding by a Mammalian receptor repertoire.

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&#x6C14;&#x5473;&#x7F16;&#x7801;&#x7531;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x53D7;&#x4F53;&#x6C47;&#x8F91; &#x300B;&#x3002;

D&#xE9;crypter le codage olfactif n&#xE9;cessite une description d&#xE9;taill&#xE9;e des ligands qui activent chaque r&#xE9;cepteur odorant (OR). Dans les syst&#xE8;mes mammif&#xE8;res, cependant, des ligands sont connus pour moins de 50 des RUP de l&#x26;#39;homme et la souris plus de 1400, ce qui limite grandement notre compr&#xE9;hension du codage olfactif. Nous avons effectu&#xE9; criblage &#xE0; haut d&#xE9;bit de 93 464 substances odorantes contre RUP exprim&#xE9;s dans des cellules h&#xE9;t&#xE9;rologues et les agonistes identifi&#xE9;s pour 52 souris et 10 RUP de l&#x26;#39;homme. Nous avons utilis&#xE9; les profils d&#x26;#39;interaction r&#xE9;sultant de d&#xE9;velopper un mod&#xE8;le pr&#xE9;dictif concernant les propri&#xE9;t&#xE9;s physico-chimiques odorants, ou des s&#xE9;quences, et leurs interactions. Nos r&#xE9;sultats constituent une base pour la traduction de substances odorantes dans les r&#xE9;ponses des neurones r&#xE9;cepteurs et pour d&#xE9;m&#xEA;ler le codage des odeurs de mammif&#xE8;res.

Odeur de codage par un R&#xE9;pertoire r&#xE9;cepteur de mammif&#xE8;re

Olfaktorische Kodierung die Entschl&uuml;sselung erfordert eine gr&uuml;ndliche Beschreibung der Liganden, die jede Odorant-Rezeptor (OR) zu aktivieren. Liganden werden jedoch in S&auml;ugetier-Systeme f&uuml;r weniger als 50 von mehr als 1400 Menschen und Maus ORs, stark begrenzen unser Verst&auml;ndnis der olfaktorische Kodierung bezeichnet. Wir spielten Hochdurchsatz-Screening von 93 Geruchsstoffe gegen 464 ORs in heterologe Zellen ausgedr&uuml;ckt und Agonisten f&uuml;r 52 Maus und 10 menschlichen ORs identifiziert. Wir die resultierende Interaktion-Profile verwendet, um ein Vorhersagemodell &uuml;ber Odoriermittel physikalisch-chemischen Eigenschaften, entwickeln OR Sequenzen und deren Interaktionen. Unsere Ergebnisse bieten eine Grundlage f&uuml;r die &Uuml;bersetzung von Ger&uuml;chen in Rezeptor Neuron Antworten und entwirren S&auml;ugetier-Geruch Coding.

Geruch Codierung durch ein S&auml;ugetier-Rezeptor-Repertoire.

Decifrazione olfattivo codifica richiede una descrizione approfondita dei ligands che attivano ogni odorant receptor (OR). Nei sistemi dei mammiferi, tuttavia, ligandi sono noti per meno di 50 di pi&ugrave; di 1400 umana e mouse ORs, limitando notevolmente la comprensione di codifica olfattive. Abbiamo eseguito high-throughput screening di 93 odorizzazione contro 464 ORs espresso nelle cellule eterologa e identificato agonisti per mouse 52 e 10 ORs umana. Abbiamo usato i profili di interazione risultante per sviluppare un modello predittivo relative propriet&agrave; fisico-chimiche odorant, OR sequenze e le loro interazioni. I nostri risultati forniscono una base per tradurre odorizzazione risposte neurone recettore e per la codificazione dei mammiferi odore unraveling.

Odore di codificazione di un repertorio di recettori dei mammiferi.

&#x55C5;&#x899A;&#x306E;&#x30A8;&#x30F3;&#x30B3;&#x30FC;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x3092;&#x89E3;&#x8AAD;&#x3059;&#x308B;&#x3068;&#x3001;&#x5404;&#x55C5;&#x899A;&#x53D7;&#x5BB9;&#x4F53;&#xFF08;OR&#xFF09;&#x3092;&#x6D3B;&#x6027;&#x5316;&#x3059;&#x308B;&#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x3092;&#x5FB9;&#x5E95;&#x7684;&#x306B;&#x8AAC;&#x660E;&#x3059;&#x308B;&#x5FC5;&#x8981;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x54FA;&#x4E73;&#x985E;&#x306E;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x3067;&#x306F;&#x3001;&#x3057;&#x304B;&#x3057;&#x3001;&#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x304C;&#x5927;&#x5E45;&#x306B;&#x55C5;&#x899A;&#x30B3;&#x30FC;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x306E;&#x6211;&#x3005;&#x306E;&#x7406;&#x89E3;&#x3092;&#x5236;&#x9650;&#x3057;&#x3001;1400&#x4EBA;&#x4EE5;&#x4E0A;&#x306E;&#x30D2;&#x30C8;&#x304A;&#x3088;&#x3073;&#x30DE;&#x30A6;&#x30B9;&#x306E;OR&#x306E;50&#x4EBA;&#x672A;&#x6E80;&#x3067;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;52&#x30DE;&#x30A6;&#x30B9;&#x3068;10&#x4EBA;&#x306E;&#x8AD6;&#x7406;&#x548C;&#x306E;&#x305F;&#x3081;&#x306E;&#x7570;&#x7A2E;&#x7D30;&#x80DE;&#x3068;&#x540C;&#x5B9A;&#x3055;&#x308C;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x3067;&#x8868;&#x3055;&#x308C;&#x308B;464&#x30AA;&#x30C3;&#x30BA;&#x6BD4;&#x306B;&#x5BFE;&#x3059;&#x308B;93&#x5302;&#x3044;&#x7269;&#x8CEA;&#x306E;&#x30CF;&#x30A4;&#x30B9;&#x30EB;&#x30FC;&#x30D7;&#x30C3;&#x30C8;&#x30B9;&#x30AF;&#x30EA;&#x30FC;&#x30CB;&#x30F3;&#x30B0;&#x3092;&#x884C;&#x3063;&#x305F;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x7269;&#x7406;&#x5316;&#x5B66;&#x7684;&#x5302;&#x3044;&#x30D7;&#x30ED;&#x30D1;&#x30C6;&#x30A3;&#x3001;&#x307E;&#x305F;&#x306F;&#x914D;&#x5217;&#x3001;&#x304A;&#x3088;&#x3073;&#x305D;&#x308C;&#x3089;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306B;&#x95A2;&#x9023;&#x4E88;&#x6E2C;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x958B;&#x767A;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x751F;&#x3058;&#x308B;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x3044;&#x307E;&#x3057;&#x305F;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x53D7;&#x5BB9;&#x4F53;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x5FDC;&#x7B54;&#x306B;&#x3068;&#x54FA;&#x4E73;&#x985E;&#x306E;&#x5302;&#x3044;&#x306E;&#x30B3;&#x30FC;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x3092;&#x89E3;&#x660E;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x4ED8;&#x81ED;&#x5264;&#x3092;&#x7FFB;&#x8A33;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x57FA;&#x790E;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;

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&#xD6C4; &#xAC01; &#xC778;&#xCF54;&#xB529; &#xD574;&#xB3C5; &#xAC01; odorant &#xC218;&#xC6A9; &#xCCB4; (OR) &#xD65C;&#xC131;&#xD654; ligands&#xC758; &#xCCA0;&#xC800; &#xD55C; &#xC124;&#xBA85;&#xC744; &#xC694;&#xAD6C; &#xD55C;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; &#xD3EC;&#xC720;&#xB958; &#xC2DC;&#xC2A4;&#xD15C; ligands &#xBBF8;&#xB9CC; 50 &#xAC1C; &#xC774;&#xC0C1;&#xC758; 1400 &#xC778;&#xAC04;&#xC758;&#xC758; &#xB9C8;&#xC6B0;&#xC2A4; ORs, &#xD06C;&#xAC8C; &#xC81C;&#xD55C; &#xD6C4; &#xAC01; &#xCF54;&#xB529;&#xC5D0; &#xB300; &#xD55C; &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xD574;&#xC5D0; &#xB300; &#xD55C; &#xC54C;&#xB824;&#xC838; &#xC788;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xB192;&#xC740; &#xCC98;&#xB9AC;&#xB7C9;&#xC744; &#xC218;&#xD589; 464 ORs &#xC0C1;&#xB300;&#xB85C; 93 odorants&#xC758; &#xBD84;&#xB9AC; &#xC140; &#xD45C;&#xD604; &#xB418; &#xACE0; 52 &#xB9C8;&#xC6B0;&#xC2A4; &#xBC0F; 10 &#xC778;&#xAC04;&#xC758; ORs agonists&#xB97C; &#xC2DD;&#xBCC4; &#xD569;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xBB3C;&#xB9AC; &#xD654;&#xD559;&#xC801; odorant &#xC18D;&#xC131;&#xC5D0; &#xAD00;&#xD55C; &#xC608;&#xCE21; &#xBAA8;&#xB378; &#xAC1C;&#xBC1C; &#xACB0;&#xACFC; &#xC0C1;&#xD638; &#xD504;&#xB85C;&#xD544; &#xC0AC;&#xC6A9; OR &#xC2DC;&#xD000;&#xC2A4; &#xBC0F; &#xADF8;&#xB4E4;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; odorants &#xC218;&#xC6A9; &#xCCB4; &#xC2E0;&#xACBD; &#xC751;&#xB2F5;&#xC73C;&#xB85C; &#xBCC0;&#xD658; &#xD558; &#xACE0; &#xBD84;&#xC5F4; &#xD3EC;&#xC720;&#xB958; &#xB0C4;&#xC0C8; &#xCF54;&#xB529;&#xC5D0; &#xB300; &#xD55C; &#xAE30;&#xCD08;&#xB97C; &#xC81C;&#xACF5; &#xD569;&#xB2C8;&#xB2E4;.

&#xB0C4;&#xC0C8;&#xB294; &#xD3EC;&#xC720;&#xB958; &#xC218;&#xC6A9; &#xCCB4; &#xB808; &#xD37C; &#xD1A0;&#xB9AC;&#xC5D0; &#xC758;&#xD574; &#xCF54;&#xB529;.

En los mam&#xED;feros, el sabor dulce est&#xE1; mediada en gran parte por un &#xFA;nico receptor. El nuevo trabajo muestra que los polimorfismos en la regi&#xF3;n promotora de un subunidad contribuir a la variaci&#xF3;n en la percepci&#xF3;n dulce en la poblaci&#xF3;n humana.

La percepci&#xF3;n del gusto: How Sweet It Is (que se transcribe por ti)

Nei mammiferi, sapore dolce &egrave; mediato in gran parte da un unico recettore. Nuovo lavoro mostra che polimorfismi nella regione del promotore di una subunit&agrave; contribuiscono alla variazione nella percezione del dolce nella popolazione umana.

Gusto percezione: how sweet it is (per essere trascritto da voi).

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&#x5473;&#x899A;&#xFF1A;&#x305D;&#x308C;&#x306F;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x30B9;&#x30A6;&#x30A3;&#x30FC;&#x30C8;&#xFF08;&#x3042;&#x306A;&#x305F;&#x304C;&#x8EE2;&#x5199;&#x3055;&#x308C;&#x308B;&#xFF09;

&#xD3EC;&#xC720;&#xB958;, &#xB2EC;&#xCF64;&#xD55C; &#xB9DB; &#xB300;&#xBD80;&#xBD84; &#xD558;&#xB098;&#xC758; &#xC218;&#xC6A9; &#xCCB4;&#xC5D0; &#xC758;&#xD574; &#xC911;&#xC7AC;&#xC785;&#xB2C8;&#xB2E4;. &#xC0C8; &#xC791;&#xC5C5; polymorphisms &#xD55C; &#xC18C; &#xB2E8;&#xC704;&#xC758; &#xD504;&#xB85C;&#xBAA8;&#xD130; &#xC601;&#xC5ED;&#xC5D0; &#xC778;&#xAC04;&#xC758; &#xC778;&#xAD6C;&#xC5D0; &#xB2EC;&#xCF64;&#xD55C; &#xC778;&#xC2DD;&#xC5D0;&#xC11C; &#xBCC0;&#xD654;&#xC5D0; &#xAE30;&#xC5EC;&#xB97C; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;.

&#xB9DB;&#xC744; &#xC9C0; &#xAC01;: (&#xB2F9;&#xC2E0;&#xC5D0; &#xC758;&#xD574; &#xBCF5;&#xC0AC;&#xD560; &#xC218;) &#xD558;&#xB294; &#xAC83;&#xC774; &#xC5BC;&#xB9C8;&#xB098; &#xB2EC;&#xCF64;&#xD55C;.

&#x54FA;&#x4E73;&#x52A8;&#x7269;&#xFF0C;&#x751C;&#x7684;&#x5473;&#x9053;&#x662F;&#x5F88;&#x5927;&#x7A0B;&#x5EA6;&#x4E0A;&#x662F;&#x7531;&#x4E00;&#x4E2A;&#x53D7;&#x4F53;&#x4ECB;&#x5BFC;&#x7684;&#x3002;&#x65B0;&#x7684;&#x5DE5;&#x4F5C;&#x663E;&#x793A;&#x4E86;&#x4E00;&#x4E2A;&#x4E9A;&#x57FA;&#x7684;&#x542F;&#x52A8;&#x5B50;&#x533A;&#x591A;&#x6001;&#x6027;&#x8D21;&#x732E;&#x751C;&#x611F;&#x77E5;&#x4EBA;&#x7C7B;&#x4EBA;&#x53E3;&#x7684;&#x53D8;&#x5316;&#x3002;

&#x5473;&#x9053;&#x611F;&#x77E5;&#xFF1A; &#xFF08;&#x6709;&#x5F85;&#x60A8;&#xFF09; &#x662F;&#x591A;&#x4E48;&#x751C;&#x3002;

In mammals, sweet taste is mediated largely by a single receptor. New work shows that polymorphisms in the promoter region of one subunit contribute to variation in sweet perception in the human population.

Taste perception: how sweet it is (to be transcribed by you).

Chez les mammif&#xE8;res, le go&#xFB;t sucr&#xE9; est m&#xE9;di&#xE9;e en grande partie par un seul r&#xE9;cepteur. De nouveaux travaux montre que les polymorphismes dans la r&#xE9;gion promotrice d&#x26;#39;un sous-unit&#xE9; de contribuer &#xE0; la variation de la perception sucr&#xE9;e dans la population humaine.

La perception du go&#xFB;t: How Sweet It Is (pour &#xEA;tre transcrit par vous)

Bei S&auml;ugetieren ist s&uuml;&szlig;er Geschmack weitgehend durch ein einzelnes Rezeptor vermittelt. Neue Arbeit zeigt, dass Polymorphismen in der Promotor-Region von einer Untereinheit zur Variation in s&uuml;&szlig;en Wahrnehmung in der menschlichen Bev&ouml;lkerung beitragen.

Schmecken Wahrnehmung: wie s&uuml;&szlig; es ist (durch Sie &uuml;bertragen werden).

&#x867D;&#x7136;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x55C5;&#x89C9; (ORs) &#x786E;&#x5B9A;&#x4E86; 15 &#x5E74;&#x591A;&#x524D;&#xFF0C;&#x6211;&#x4EEC;&#x4ECD;&#x7136;&#x4E0D;&#x660E;&#x767D;&#x6C14;&#x5473;&#x5206;&#x5B50;&#x4E0E;&#x53E3;&#x670D;&#x8865;&#x6DB2;&#x76D0;&#x5206;&#x5B50;&#x6C34;&#x5E73;&#x7684;&#x4EA4;&#x4E92;&#x65B9;&#x5F0F;&#x3002;&#x4EE5;&#x524D;&#x5BF9;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7684;&#x53E3;&#x670D;&#x8865;&#x6DB2;&#x76D0;&#x7684;&#x7814;&#x7A76;&#x68C0;&#x9A8C;&#x4E86;&#x51E0;&#x4E2A;&#x53E3;&#x670D;&#x8865;&#x6DB2;&#x76D0;&#x5BF9;&#x8BB8;&#x591A;&#x6C14;&#x5473;&#x3002;&#x4E00;&#x4E9B;&#x57FA;&#x672C;&#x5C5E;&#x6027;&#x7684;&#x55C5;&#x89C9;&#x7CFB;&#x7EDF;&#xFF0C;&#x4F46;&#x662F;&#xFF0C;&#x4E0E;&#x8BB8;&#x591A;&#x5316;&#x5B66;&#x7ED3;&#x6784;&#x4E0D;&#x540C;&#x6C14;&#x5473;&#x9700;&#x8981;&#x5E7F;&#x6CDB;&#x591A;&#x6837;&#x7684;&#x53E3;&#x670D;&#x8865;&#x6DB2;&#x76D0;&#x5C0F;&#x7EC4;&#x7684;&#x8C03;&#x67E5;&#x3002;&#x4EE5;&#x524D;&#xFF0C;&#x6211;&#x4EEC;&#x786E;&#x5B9A;&#x6216;&#x8F85;&#x52A9;&#x86CB;&#x767D;&#x3001; &#x53D7;&#x4F53;&#x8FD0;&#x8F93;&#x86CB;&#x767D; (RTP) 1 &#x548C; RTP2&#x3002;&#x4ED6;&#x4EEC;&#x90FD;&#x8868;&#x793A;&#x5177;&#x4F53;&#x7684;&#x55C5;&#x89C9;&#x795E;&#x7ECF;&#x5143;&#x3001; &#x5173;&#x8054;&#x6216;&#x86CB;&#x767D;&#x8D28;&#xFF0C;&#x548C;&#x4FBF;&#x5229;&#x6216;&#x8D29;&#x5356;&#x5230;&#x7EC6;&#x80DE;&#x819C;&#x65F6;&#x5728;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7EC6;&#x80DE;&#x682A; coexpressed&#x3002;&#x4F7F;&#x7528;&#x6B64;&#x65B9;&#x6CD5;&#xFF0C;&#x9AD8;&#x901A;&#x91CF;&#x7B5B;&#x9009;&#x4F7F;&#x7528;&#x5927;&#x6C47;&#x8F91; &#x300B; &#x54FA;&#x4E73;&#x52A8;&#x7269;&#x53E3;&#x670D;&#x8865;&#x6DB2;&#x76D0;&#x662F;&#x73B0;&#x5728;&#x53EF;&#x80FD;&#x3002;&#x6FC0;&#x6D3B;&#x914D;&#x7F6E;&#x6587;&#x4EF6;&#x53EF;&#x7528;&#x4E8E;&#x5236;&#x5B9A;&#x6709;&#x5173;&#x7406;&#x5316;&#x6C14;&#x5473;&#x5C5E;&#x6027;&#x3001; &#x53D7;&#x4F53;&#x5E8F;&#x5217;&#x548C;&#x76F8;&#x4E92;&#x5173;&#x7CFB;&#xFF0C;&#x4F7F;&#x6211;&#x4EEC;&#x80FD;&#x591F;&#x9884;&#x6D4B;&#x65B0;&#x578B;&#x53D7;&#x4F53;&#x54CD;&#x5E94;&#x6D4B;&#x8BD5;&#x7684;&#x6C14;&#x5473;&#x548C;&#x65B0;&#x9896;&#x7684;&#x6C14;&#x5473;&#x6D4B;&#x8BD5;&#x53D7;&#x4F53;&#x53CD;&#x5E94;&#x7684;&#x9884;&#x6D4B;&#x6A21;&#x578B;&#x3002;&#x8FD9;&#x6837;&#x505A;&#x5C06;&#x63D0;&#x4F9B;&#x4E00;&#x4E2A;&#x57FA;&#x7840;&#x5BF9;&#x4E8E;&#x7406;&#x89E3;&#x5982;&#x4F55;&#x7ED3;&#x6784;&#x4E0A;&#x7684;&#x4E0D;&#x540C;&#x6C14;&#x5473;&#x5206;&#x5B50;&#x6FC0;&#x6D3B;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x6216;&#x6C47;&#x8F91; &#x300B;&#x3002;&#x540C;&#x6837;&#x5730;&#xFF0C;&#x7281;&#x9F3B;&#x53D7;&#x4F53;&#xFF0C;V1Rs &#x548C; V2Rs&#xFF0C;&#x4E24;&#x4E2A;&#x5BB6;&#x5EAD;&#x4E5F;&#x662F;&#x6781;&#x96BE;&#x5728;&#x5F02;&#x79CD;&#x7EC6;&#x80DE;&#x529F;&#x80FD;&#x8868;&#x8FBE;&#x7684;&#x3002;&#x7136;&#x800C;&#xFF0C;RTP &#x5BB6;&#x5EAD;&#x6210;&#x5458;&#x4E0E; V1Rs &#x6216; V2Rs &#x7684;&#x5171;&#x8868;&#x8FBE;&#x4F3C;&#x4E4E;&#x5E76;&#x4E0D;&#x4FBF;&#x5229;&#x8D29;&#x8FD0;&#x7684;&#x53D7;&#x4F53;&#x86CB;&#x767D;&#x8D28;&#x3002;&#x8FD9;&#x4E00;&#x53D1;&#x73B0;&#x8868;&#x660E;&#x7281;&#x9F3B;&#x5668;&#x5B98;&#x72EC;&#x7279;&#x7684;&#x819C;&#x86CB;&#x767D;&#x7684;&#x751F;&#x7269;&#x5408;&#x6210;&#x9014;&#x5F84;&#x3002;

&#x8D29;&#x8FD0;&#x7684;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x5316;&#x5B66;&#x611F;&#x53D7;&#x4F53;&#x7684;&#x8F6C;&#x8FD0;&#x53D7;&#x4F53;&#x86CB;&#x767D;&#x3002;

Although mammalian odorant receptors (ORs) were identified more than 15 years ago, we still do not understand how odorant molecules interact with ORs at a molecular level. Previous studies of mammalian ORs have tested few ORs against many odorants. Some fundamental properties of the olfactory system, however, require investigation of a wide panel of diverse ORs with many chemically diverse odorants. Previously, we identified OR accessory proteins, receptor-transporting protein (RTP) 1 and RTP2. They are expressed specifically in olfactory neurons, are associated with OR proteins, and facilitate the OR trafficking to the plasma membrane when coexpressed in mammalian cell lines. With this approach, high-throughput screening using a large repertoire of mammalian ORs is now possible. The activation profiles can be used to develop a predictive model relating physicochemical odorant properties, receptor sequences, and their interactions, enabling us to predict a tested receptor's response to a novel odorant and a novel receptor's response to a tested odorant. Doing so will provide a basis for understanding how structurally diverse odorant molecules activate the mammalian OR repertoire. Similarly, two families of vomeronasal receptors, V1Rs and V2Rs, are also notoriously difficult to functionally express in heterologous cells. However, coexpression of the RTP family members with V1Rs or V2Rs does not seem to facilitate trafficking of the receptor proteins. This finding suggests that the vomeronasal organ has a unique biosynthetic pathway for membrane proteins.

Trafficking of mammalian chemosensory receptors by receptor-transporting proteins.

Bien que les r&#xE9;cepteurs olfactifs de mammif&#xE8;res (RUP) ont &#xE9;t&#xE9; identifi&#xE9;s plus de 15 ans, nous n&#x26;#39;avons toujours pas comprendre comment les mol&#xE9;cules odorantes interagir avec les RUP au niveau mol&#xE9;culaire. Des &#xE9;tudes ant&#xE9;rieures des RUP mammif&#xE8;res ont test&#xE9; quelques RUP contre odorants nombreux. Certaines propri&#xE9;t&#xE9;s fondamentales du syst&#xE8;me olfactif, toutefois, r&#xE9;clamer une enqu&#xEA;te sur un large panel des RUP diverse avec de nombreuses substances odorantes chimiquement divers. Auparavant, nous avons identifi&#xE9; OU prot&#xE9;ines accessoires, le r&#xE9;cepteur de transport de prot&#xE9;ines (RTP) 1 et RTP2. Ils sont exprim&#xE9;s sp&#xE9;cifiquement dans les neurones olfactifs, sont associ&#xE9;s &#xE0; ou de prot&#xE9;ines, et de faciliter la ou le trafic vers la membrane plasmique lors coexprim&#xE9; dans des lign&#xE9;es cellulaires de mammif&#xE8;res. Avec cette approche, criblage &#xE0; haut d&#xE9;bit en utilisant un large r&#xE9;pertoire des RUP mammif&#xE8;res est maintenant possible. Les profils d&#x26;#39;activation peut &#xEA;tre utilis&#xE9;e pour d&#xE9;velopper un mod&#xE8;le pr&#xE9;dictif concernant les propri&#xE9;t&#xE9;s physico-chimiques odorants, des s&#xE9;quences de r&#xE9;cepteurs, et de leurs interactions, ce qui nous permet de pr&#xE9;dire la r&#xE9;ponse d&#x26;#39;un r&#xE9;cepteur test&#xE9; &#xE0; une substance odorante roman et la r&#xE9;ponse d&#x26;#39;un nouveau r&#xE9;cepteur &#xE0; une substance odorante test&#xE9;. Cela fournira une base pour comprendre comment les mol&#xE9;cules odorantes structurellement diverses activer le mammif&#xE8;re ou le r&#xE9;pertoire. De m&#xEA;me, deux familles de r&#xE9;cepteurs vom&#xE9;ronasal, V1Rs et V2Rs, sont aussi notoirement difficile &#xE0; exprimer fonctionnellement dans les cellules h&#xE9;t&#xE9;rologues. Cependant, la coexpression des membres de la famille RTP avec V1Rs ou V2Rs ne semble pas faciliter le trafic des prot&#xE9;ines r&#xE9;ceptrices. Cette constatation sugg&#xE8;re que l&#x26;#39;organe vom&#xE9;ronasal est une voie de biosynth&#xE8;se unique pour les prot&#xE9;ines membranaires.

La traite des mammif&#xE8;res r&#xE9;cepteurs chimiosensoriels par Receptor-le transport des prot&#xE9;ines

Obwohl S&auml;ugetier-Odorant-Rezeptoren (ORs) vor mehr als 15 Jahren identifiziert wurden, noch verstehen wir nicht wie Odoriermittel Molek&uuml;le mit ORs auf molekularer Ebene interagieren. Fr&uuml;here Studien von S&auml;ugetier-ORs haben einige ORs gegen viele Geruchsstoffe getestet. Einige grundlegenden Eigenschaften des olfaktorischen Systems, erfordern jedoch die Untersuchung eines breiten Bereichs von diversen ORs mit vielen chemisch unterschiedliche Geruchsstoffe. Zuvor haben wir festgestellt, OR Zubeh&ouml;r Proteine, Rezeptor-transportierende Protein (RTP) 1 und RTP2. Sie sind speziell in olfaktorischen Neuronen exprimiert, OR Proteine zugeordnet sind und erleichtern den OR-Handel an der Plasmamembran beim coexpressed in S&auml;ugetier-Zellformen. Bei diesem Ansatz ist Hochdurchsatz-screening mit ein gro&szlig;es Repertoire an S&auml;ugetieren ORs jetzt m&ouml;glich. Die Aktivierungs-Profile k&ouml;nnen verwendet werden, ein Vorhersagemodell &uuml;ber Odoriermittel physikalisch-chemischen Eigenschaften, Rezeptor-Sequenzen und ihre Interaktionen, die es uns erm&ouml;glicht, eine getestete Rezeptor-Reaktion auf eine neuartige Odoriermittel und eine neuartige Rezeptor-Reaktion auf eine getestete Odoriermittel Vorhersagen zu entwickeln. Damit wird eine Grundlage bilden f&uuml;r das Verst&auml;ndnis wie strukturell unterschiedlichen Odoriermittel Molek&uuml;le aktivieren das S&auml;ugetier-OR-Repertoire. Ebenso sind zwei Familien Vomeronasal Rezeptoren, V1Rs und V2Rs, auch notorisch schwierig mit funktional heterologe Zellen ausgedr&uuml;ckt. Jedoch scheint Coexpression der RTP-Familienmitglieder mit V1Rs oder V2Rs nicht zur Erleichterung des Menschenhandels der Rezeptor-Proteine. Dieser Befund legt nahe, dass das Vomeronasal Organ eine einzigartige biosynthetischen Bahn f&uuml;r Membranproteine hat.

Menschenhandel von S&auml;ugetieren chemosensory Rezeptoren durch Rezeptor-transportierende Proteine.

Sebbene nei mammiferi odorant recettori (ORs) sono stati identificati pi&ugrave; di 15 anni fa, ancora non capiamo come odorant molecole interagiscono con ORs a livello molecolare. Precedenti studi di ORs mammiferi hanno testato ORs pochi contro molti odorifere. Alcune propriet&agrave; fondamentali del sistema olfattivo, tuttavia, richiedono indagini di un ampio pannello di ORs diversificata con molti odorizzazione chimicamente diverse. In precedenza, abbiamo identificato o proteine accessorie, proteina recettore-trasporto (RTP) 1 e RTP2. Essi sono espressi specificamente in neuroni olfattivi, sono associati a proteine OR e facilitare il traffico OR a membrana del plasma quando coespressi nelle linee di cellule di mammifero. Con questo approccio, high-throughput screening utilizzando un vasto repertorio di mammiferi ORs &egrave; ora possibile. I profili di attivazione possono essere utilizzati per sviluppare un modello predittivo relative propriet&agrave; fisico-chimiche odorant, sequenze dei recettori e loro interazioni, che ci permette di predire la risposta del recettore testato a un romanzo odorant e risposta del recettore romanzo a una odorant testati. In questo modo fornir&agrave; una base per la comprensione odorant come strutturalmente diverse molecole attivare il repertorio dei mammiferi OR. Analogamente, due famiglie di recettori vomeronasal, V1Rs e V2Rs, inoltre sono notoriamente difficili da funzionalmente esprimere nelle cellule eterologa. Tuttavia, coexpression dei membri della famiglia RTP con V1Rs o V2Rs non sembra facilitare il traffico delle proteine recettore. Questa scoperta suggerisce che l&#39;organo vomeronasale presenta un unico percorso biosintetico per le proteine di membrana.

Traffico dei ricevitori chemosensory mammiferi da proteine di trasporto del recettore.

&#x54FA;&#x4E73;&#x985E;&#x306E;&#x55C5;&#x899A;&#x53D7;&#x5BB9;&#x4F53;&#xFF08;ORS&#xFF09;&#x306F;15&#x5E74;&#x4EE5;&#x4E0A;&#x524D;&#x306B;&#x540C;&#x5B9A;&#x3055;&#x308C;&#x305F;&#x304C;&#x3001;&#x6211;&#x3005;&#x306F;&#x307E;&#x3060;&#x5302;&#x3044;&#x5206;&#x5B50;&#x304C;&#x5206;&#x5B50;&#x30EC;&#x30D9;&#x30EB;&#x3067;&#x306E;&#x8AD6;&#x7406;&#x548C;&#x3068;&#x306E;&#x5BFE;&#x8A71;&#x65B9;&#x6CD5;&#x3092;&#x7406;&#x89E3;&#x3057;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x54FA;&#x4E73;&#x985E;&#x306E;OR&#x306E;&#x4EE5;&#x524D;&#x306E;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x591A;&#x304F;&#x306E;&#x5302;&#x3044;&#x7269;&#x8CEA;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x8AD6;&#x7406;&#x548C;&#x3092;&#x30C6;&#x30B9;&#x30C8;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x55C5;&#x899A;&#x7CFB;&#x306E;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x57FA;&#x672C;&#x7684;&#x306A;&#x6027;&#x8CEA;&#x306F;&#x3001;&#x3057;&#x304B;&#x3057;&#x3001;&#x591A;&#x304F;&#x306E;&#x5316;&#x5B66;&#x7684;&#x306B;&#x591A;&#x69D8;&#x306A;&#x5302;&#x3044;&#x7269;&#x8CEA;&#x306E;&#x591A;&#x69D8;&#x306A;OR&#x306E;&#x30EF;&#x30A4;&#x30C9;&#x30D1;&#x30CD;&#x30EB;&#x306E;&#x8ABF;&#x67FB;&#x3092;&#x3059;&#x308B;&#x5FC5;&#x8981;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x4EE5;&#x524D;&#x3001;&#x6211;&#x3005;&#x306F;&#x53D7;&#x5BB9;&#x4F53;&#x8F38;&#x9001;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#xFF08;RTP&#xFF09;1 RTP2&#x3001;&#x540C;&#x5B9A;&#x307E;&#x305F;&#x306F;&#x30A2;&#x30AF;&#x30BB;&#x30B5;&#x30EA;&#x30FC;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x3002;&#x5F7C;&#x3089;&#x306F;&#x3001;&#x55C5;&#x899A;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x3001;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x307E;&#x305F;&#x306F;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306B;&#x7279;&#x7570;&#x7684;&#x306B;&#x767A;&#x73FE;&#x3001;&#x304A;&#x3088;&#x3073;&#x54FA;&#x4E73;&#x52D5;&#x7269;&#x7D30;&#x80DE;&#x682A;&#x3067;&#x767A;&#x73FE;&#x3055;&#x305B;&#x305F;&#x3068;&#x304D;&#x306B;&#x7D30;&#x80DE;&#x819C;&#x306B;OR&#x4EBA;&#x8EAB;&#x58F2;&#x8CB7;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x3067;&#x306F;&#x3001;&#x54FA;&#x4E73;&#x985E;&#x306E;OR&#x306E;&#x5927;&#x898F;&#x6A21;&#x306A;&#x30EC;&#x30D1;&#x30FC;&#x30C8;&#x30EA;&#x30FC;&#x3092;&#x7528;&#x3044;&#x305F;&#x30CF;&#x30A4;&#x30B9;&#x30EB;&#x30FC;&#x30D7;&#x30C3;&#x30C8;&#x30B9;&#x30AF;&#x30EA;&#x30FC;&#x30CB;&#x30F3;&#x30B0;&#x304C;&#x53EF;&#x80FD;&#x306B;&#x306A;&#x308A;&#x307E;&#x3057;&#x305F;&#x3002;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x306F;&#x3001;&#x79C1;&#x305F;&#x3061;&#x306F;&#x65B0;&#x305F;&#x306A;&#x5302;&#x3044;&#x3068;&#x55C5;&#x899A;&#x30C6;&#x30B9;&#x30C8;&#x306B;&#x65B0;&#x305F;&#x306A;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x5FDC;&#x7B54;&#x306B;&#x30C6;&#x30B9;&#x30C8;&#x3055;&#x308C;&#x305F;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x5FDC;&#x7B54;&#x3092;&#x4E88;&#x6E2C;&#x3067;&#x304D;&#x308B;&#x3088;&#x3046;&#x306B;&#x3001;&#x7269;&#x7406;&#x5316;&#x5B66;&#x7684;&#x5302;&#x3044;&#x7279;&#x6027;&#x3001;&#x53D7;&#x5BB9;&#x4F53;&#x914D;&#x5217;&#x3001;&#x304A;&#x3088;&#x3073;&#x305D;&#x308C;&#x3089;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306B;&#x95A2;&#x9023;&#x4E88;&#x6E2C;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x958B;&#x767A;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x305D;&#x3046;&#x3059;&#x308B;&#x3053;&#x3068;&#x3067;&#x3001;&#x591A;&#x69D8;&#x306A;&#x5302;&#x3044;&#x5206;&#x5B50;&#x306F;&#x3001;&#x54FA;&#x4E73;&#x52D5;&#x7269;&#x307E;&#x305F;&#x306F;&#x30EC;&#x30D1;&#x30FC;&#x30C8;&#x30EA;&#x30FC;&#x3092;&#x6709;&#x52B9;&#x306B;&#x3059;&#x308B;&#x65B9;&#x6CD5;&#x3001;&#x69CB;&#x9020;&#x7684;&#x306B;&#x7406;&#x89E3;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x57FA;&#x790E;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;&#x540C;&#x69D8;&#x306B;&#x3001;&#x92E4;&#x9F3B;&#x53D7;&#x5BB9;&#x4F53;&#x3001;V1Rs&#x3068;V2Rs&#x306E;2&#x3064;&#x306E;&#x30D5;&#x30A1;&#x30DF;&#x30EA;&#x30FC;&#x306F;&#x307E;&#x305F;&#x3001;&#x6A5F;&#x80FD;&#x7684;&#x306B;&#x7570;&#x7A2E;&#x7D30;&#x80DE;&#x3067;&#x767A;&#x73FE;&#x306F;&#x975E;&#x5E38;&#x306B;&#x56F0;&#x96E3;&#x3067;&#x3042;&#x308B;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;V1Rs&#x307E;&#x305F;&#x306F;V2Rs&#x3068;RTP&#x306E;&#x5BB6;&#x65CF;&#x306E;&#x5171;&#x767A;&#x73FE;&#x306F;&#x3001;&#x53D7;&#x5BB9;&#x4F53;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x8F38;&#x9001;&#x3092;&#x5BB9;&#x6613;&#x306B;&#x3057;&#x3066;&#x3044;&#x306A;&#x3044;&#x3088;&#x3046;&#x3067;&#x3059;&#x3002;&#x3053;&#x306E;&#x77E5;&#x898B;&#x306F;&#x3001;&#x92E4;&#x9F3B;&#x5668;&#x5B98;&#x306E;&#x819C;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x56FA;&#x6709;&#x306E;&#x751F;&#x5408;&#x6210;&#x7D4C;&#x8DEF;&#x3092;&#x6301;&#x3064;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x53D7;&#x5BB9;&#x4F53;&#x8F38;&#x9001;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306B;&#x3088;&#x3063;&#x3066;&#x54FA;&#x4E73;&#x985E;&#x306E;&#x55C5;&#x899A;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x30C8;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30AD;&#x30F3;&#x30B0;

&#xD3EC;&#xC720;&#xB958; odorant &#xC218;&#xC6A9; &#xCCB4; (ORs) 15 &#xC5EC; &#xB144; &#xC804; &#xBC1C;&#xACAC; &#xD588;&#xB2E4;, &#xBE44;&#xB85D; &#xC6B0;&#xB9AC;&#xAC00; &#xC544;&#xC9C1;&#xB3C4; &#xC774;&#xD574;&#xAC00; &#xC548; odorant &#xBD84;&#xC790; ORs &#xBD84;&#xC790; &#xC218;&#xC900;&#xC5D0;&#xC11C; &#xC0C1;&#xD638; &#xC791;&#xC6A9; &#xD558;&#xB294; &#xBC29;&#xBC95;. &#xD3EC;&#xC720;&#xB958; Ors&#xC758; &#xC774;&#xC804; &#xC5F0;&#xAD6C;&#xB294; &#xB9CE;&#xC740; odorants&#xC5D0; &#xB300; &#xD55C; &#xBA87; &#xAC00;&#xC9C0; Ors&#xB97C; &#xD14C;&#xC2A4;&#xD2B8; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; &#xD6C4; &#xAC01; &#xC2DC;&#xC2A4;&#xD15C;&#xC758; &#xC77C;&#xBD80; &#xAE30;&#xBCF8; &#xC18D;&#xC131;&#xC740; &#xB9CE;&#xC740; &#xD654;&#xD559;&#xC801;&#xC73C;&#xB85C; &#xB2E4;&#xC591; &#xD55C; odorants&#xC640; &#xD568;&#xAED8; &#xB2E4;&#xC591; &#xD55C; Ors&#xC758; &#xB113;&#xC740; &#xD328;&#xB110;&#xC758; &#xC870;&#xC0AC; &#xD544;&#xC694;. &#xC774;&#xC804;&#xC5D0;, &#xB610;&#xB294; &#xC561;&#xC138;&#xC11C;&#xB9AC; &#xB2E8;&#xBC31;&#xC9C8;, &#xC218;&#xC6A9; &#xCCB4;&#xB97C; &#xC6B4;&#xBC18; &#xD558;&#xB294; &#xB2E8;&#xBC31;&#xC9C8; (RTP) 1 &#xBC0F; RTP2 &#xD30C;&#xC545;. &#xADF8;&#xB4E4;&#xC740; &#xD6C4; &#xAC01; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xAD6C;&#xCCB4;&#xC801;&#xC73C;&#xB85C; &#xD45C;&#xD604; &#xB418;&#xB294; OR &#xB2E8;&#xBC31;&#xC9C8; &#xC5F0;&#xAD00; &#xBC0F; &#xD3EC;&#xC720;&#xB958; &#xC138;&#xD3EC;&#xC5D0; coexpressed &#xB54C; &#xD50C;&#xB77C;&#xC988;&#xB9C8; &#xBA64;&#xBE0C;&#xB808;&#xC778; OR &#xBC00;&#xB9E4; &#xCD09;&#xC9C4;. &#xC774; &#xBC29;&#xBC95;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xCC28;&#xB2E8; &#xD558;&#xB294; &#xB192;&#xC740; &#xCC98;&#xB9AC;&#xB7C9; &#xD3EC;&#xC720;&#xB958; Ors&#xC758; &#xD070; &#xB808; &#xD37C; &#xD1A0;&#xB9AC; &#xC9C0;&#xAE08; &#xAC00;&#xB2A5; &#xD558;&#xB2E4;. &#xD65C;&#xC131;&#xD654; &#xD504;&#xB85C;&#xD544; &#xBB3C;&#xB9AC; odorant &#xC18D;&#xC131;, &#xC218;&#xC6A9; &#xCCB4; &#xC2DC;&#xD000;&#xC2A4; &#xBC0F; &#xC6B0;&#xB9AC; &#xC18C;&#xC124; odorant &#xD14C;&#xC2A4;&#xD2B8; &#xC218;&#xC6A9; &#xCCB4; &#xBC18;&#xC751; &#xBC0F; &#xD14C;&#xC2A4;&#xD2B8; odorant &#xC18C;&#xC124; &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xBC18;&#xC751; &#xC608;&#xCE21;&#xD560; &#xC218; &#xC788;&#xAC8C; &#xD558;&#xB294; &#xADF8;&#xB4E4;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xAD00;&#xD55C; &#xC608;&#xCE21; &#xBAA8;&#xB378;&#xC744; &#xAC1C;&#xBC1C; &#xD558;&#xAE30; &#xC704;&#xD574; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB807;&#xAC8C; &#xD558;&#xB294; &#xAC83;&#xC740; &#xAE30;&#xCD08;&#xB97C; &#xC81C;&#xACF5; &#xAC83;&#xC785;&#xB2C8;&#xB2E4; &#xC5B4;&#xB5BB;&#xAC8C; &#xAD6C;&#xC870;&#xC801;&#xC73C;&#xB85C; &#xB2E4;&#xC591; &#xD55C; odorant &#xC774;&#xD574; &#xD558;&#xAE30; &#xC704;&#xD55C; &#xBD84;&#xC790; &#xD3EC;&#xC720;&#xB958; OR &#xB808; &#xD37C; &#xD1A0;&#xB9AC;&#xB97C; &#xD65C;&#xC131;&#xD654; &#xD569;&#xB2C8;&#xB2E4;. &#xB9C8;&#xCC2C;&#xAC00;&#xC9C0;&#xB85C;, V1Rs &#xBC0F; V2Rs, vomeronasal &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xB450; &#xAC00;&#xC871; &#xC545;&#xBA85; &#xAE30;&#xB2A5;&#xC801;&#xC73C;&#xB85C; &#xBD84;&#xB9AC; &#xC140;&#xC5D0;&#xC11C; &#xD45C;&#xD604; &#xD558;&#xAE30; &#xC5B4;&#xB824;&#xC6B4; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, V1Rs &#xB610;&#xB294; v2rs&#xC640; RTP &#xAC00;&#xC871; &#xAD6C;&#xC131;&#xC6D0;&#xC758; coexpression &#xC218;&#xC6A9; &#xCCB4; &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xC778;&#xC2E0; &#xB9E4;&#xB9E4;&#xB97C; &#xCD09;&#xC9C4; &#xD558;&#xC9C0; &#xC54A;&#xB294; &#xAC83;. &#xC774; &#xCC3E;&#xB294; vomeronasal &#xAE30;&#xAD00; &#xB9C9; &#xB2E8;&#xBC31;&#xC9C8;&#xC5D0; &#xB300; &#xD55C; &#xB3C5;&#xD2B9;&#xD55C; &#xC0DD; &#xD569;&#xC131; &#xD1B5;&#xB85C; &#xB098;&#xC654;&#xB2E4;.

&#xD3EC;&#xC720;&#xB958; chemosensory &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC218;&#xC6A9; &#xCCB4; &#xC218;&#xC1A1; &#xB2E8;&#xBC31;&#xC9C8;&#xC5D0; &#xC758;&#xD574; &#xC778;&#xC2E0; &#xB9E4;&#xB9E4;.

A pesar de los receptores olfativos de mam&#xED;feros (OR) se identificaron m&#xE1;s de 15 a&#xF1;os, todav&#xED;a no entiendo c&#xF3;mo las mol&#xE9;culas odor&#xED;feras interactuar con OR a nivel molecular. Los estudios previos de las RUP de mam&#xED;feros han puesto a prueba las RUP pocos contra muchos olores. Algunas de las propiedades fundamentales del sistema olfativo, sin embargo, requieren una investigaci&#xF3;n de un amplio panel de las RUP con muchos diversos olores diversos qu&#xED;micamente. Anteriormente, hemos identificado o prote&#xED;nas accesorias, los receptores de la prote&#xED;na transportadora (RTP) 1 y RTP 2. Ellos se expresan espec&#xED;ficamente en las neuronas olfativas, est&#xE1;n asociados con o prote&#xED;nas, y facilitar el tr&#xE1;fico de O a la membrana plasm&#xE1;tica cuando coexpressed en l&#xED;neas celulares de mam&#xED;feros. Con este enfoque, selecci&#xF3;n de alto rendimiento con un gran repertorio de las RUP de mam&#xED;feros es ahora posible. Los perfiles de activaci&#xF3;n puede ser utilizado para desarrollar un modelo predictivo sobre las propiedades f&#xED;sico-qu&#xED;micas de olor, las secuencias de los receptores, y sus interacciones, lo que nos permite predecir la respuesta de un receptor probado a un olor nuevo y la respuesta de un nuevo receptor de un olor a prueba. Si lo hace, proporcionar una base para la comprensi&#xF3;n de c&#xF3;mo estructuralmente diversas mol&#xE9;culas odorantes activar el mam&#xED;fero o repertorio. Del mismo modo, dos familias de receptores vomeronasal, V1Rs y V2Rs, tambi&#xE9;n son notoriamente dif&#xED;ciles de expresar funcionalmente en c&#xE9;lulas heter&#xF3;logas. Sin embargo, la co-expresi&#xF3;n de los miembros de la familia RTP con V1Rs o V2Rs no parece facilitar el tr&#xE1;fico de las prote&#xED;nas receptoras. Este hallazgo sugiere que el &#xF3;rgano vomeronasal tiene una &#xFA;nica v&#xED;a de bios&#xED;ntesis de prote&#xED;nas de la membrana.

El tr&#xE1;fico de mam&#xED;feros receptores Quimiosensoriales por prote&#xED;nas transportadoras del receptor-

Although odour perception impacts food preferences, the effect of genotypic variation of odorant receptors (ORs) on the sensory perception of food is unclear. Human OR7D4 responds to androstenone, and genotypic variation in OR7D4 predicts variation in the perception of androstenone. Since androstenone is naturally present in meat derived from male pigs, we asked whether OR7D4 genotype correlates with either the ability to detect androstenone or the evaluation of cooked pork tainted with varying levels of androstenone within the naturally-occurring range. Consistent with previous findings, subjects with two copies of the functional OR7D4 RT variant were more sensitive to androstenone than subjects carrying a non-functional OR7D4 WM variant. When pork containing varying levels of androstenone was cooked and tested by sniffing and tasting, subjects with two copies of the RT variant tended to rate the androstenone-containing meat as less favourable than subjects carrying the WM variant. Our data is consistent with the idea that OR7D4 genotype predicts the sensory perception of meat containing androstenone and that genetic variation in an odorant receptor can alter food preferences.

Genetic variation of an odorant receptor OR7D4 and sensory perception of cooked meat containing androstenone.

The ability to detect many odors varies among individuals; however, the contribution of genotype to this variation has been assessed for relatively few compounds. We have identified a genetic basis for the ability to detect the flavor compound cis-3-hexen-1-ol. This compound is typically described as "green grassy" or the smell of "cut grass," with variation in the ability to detect it linked to single nucleotide polymorphisms (SNPs) in a region on human chromosome 6 containing 25 odorant receptor genes. We have sequenced the coding regions of all 25 receptors across an ethnically mixed population of 52 individuals and identified 147 sequence variants. We tested these for association with cis-3-hexen-1-ol detection thresholds and found 3 strongly associated SNPs, including one found in a functional odorant receptor (rs28757581 in OR2J3). In vitro assays of 13 odorant receptors from the region identified 3 receptors that could respond to cis-3-hexen-1-ol, including OR2J3. This gene contained 5 predicted haplotypes across the 52 individuals. We tested all 5 haplotypes in vitro and several amino acid substitutions on their own, such as rs28757581 (T113A). Two amino acid substitutions, T113A and R226Q, impaired the ability of OR2J3 to respond to cis-3-hexen-1-ol, and together these two substitutions effectively abolished the response to the compound. The haplotype of OR2J3 containing both T113A and R226Q explains 26.4% of the variation in cis-3-hexen-1-ol detection in our study cohort. Further research is required to examine whether OR2J3 haplotypes explain variation in perceived flavor experience and the consumption of foods containing cis-3-hexen-1-ol.

Genetic variation in the odorant receptor OR2J3 is associated with the ability to detect the "grassy" smelling odor, cis-3-hexen-1-ol.

The mammalian odorant receptor (OR) repertoire is an attractive model to study evolution, because ORs have been subjected to rapid evolution between species, presumably caused by changes of the olfactory system to adapt to the environment. However, functional assessment of ORs in related species remains largely untested. Here we investigated the functional properties of primate and rodent ORs to determine how well evolutionary distance predicts functional characteristics. Using human and mouse ORs with previously identified ligands, we cloned 18 OR orthologs from chimpanzee and rhesus macaque and 17 mouse-rat orthologous pairs that are broadly representative of the OR repertoire. We functionally characterized the in vitro responses of ORs to a wide panel of odors and found similar ligand selectivity but dramatic differences in response magnitude. 87% of human-primate orthologs and 94% of mouse-rat orthologs showed differences in receptor potency (EC50) and/or efficacy (dynamic range) to an individual ligand. Notably dN/dS ratio, an indication of selective pressure during evolution, does not predict functional similarities between orthologs. Additionally, we found that orthologs responded to a common ligand 82% of the time, while human OR paralogs of the same subfamily responded to the common ligand only 33% of the time. Our results suggest that, while OR orthologs tend to show conserved ligand selectivity, their potency and/or efficacy dynamically change during evolution, even in closely related species. These functional changes in orthologs provide a platform for examining how the evolution of ORs can meet species-specific demands.

Functional evolution of mammalian odorant receptors.

Humans have approximately 400 intact olfactory receptors (ORs). Among this set there are a large number of variations between individuals, a subset of which affects receptor function and can lead to interindividual variation in olfactory perception. Technological progress and cost erosion in next-generation sequencing have given us the opportunity to determine the sequence of the entire OR gene set with high fidelity and to measure the extent of variation in this functional module across many individuals. Given that whole genome sequencing remains prohibitively expensive for this purpose, especially since the OR sub-genome represents only ~0.0125 % of the human genome, we have designed a targeted capture method to enrich the OR for next-generation sequencing, which we describe here. Using this method we have been able to sequence an individual's OR sub-genome with high coverage, enabling us to identify variation with high sensitivity and specificity. This method can be used to accurate assess the amount of variability in this module and to identify the functional role of individual ORs in olfactory perception.

Next-generation sequencing of the human olfactory receptors.

Humans have ~400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals have functional differences at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high-affinity in vitro agonist guaiacol but do not explain phenotype variation for the lower-affinity agonists vanillin and ethyl vanillin.

Joel D. Mainland

Monell Chemical Senses Center

High-throughput Analysis of Mammalian Olfactory Receptors: Measurement of Receptor Activation via Luciferase Activity