5.5 : Cholinergic Receptors: Muscarinic

The pharmacological actions of acetylcholine are elicited via its binding to two families of cholinergic receptors or cholinoceptors, namely, muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors and have five subtypes, M₁–M₅. All mAChR subtypes are activated by acetylcholine and blocked by the antagonist, atropine.

The subtypes M₁, M_3, and M₅ couple with the G_q subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca²⁺. Activation of PLC proceeds with the production of secondary messengers, inositol-1,4,5-phosphate (IP₃) and diacylglycerol (DAG). IP₃ ion-channel receptor stimulation releases intracellular Ca²⁺ from the endoplasmic reticulum. DAG and Ca²⁺ activate protein kinase C (PKC), which phosphorylates protein to generate physiological effects.

The subtypes M₂ and M₄ couple with the G_i subunit to decrease adenylyl cyclase activity and increase K⁺ conductance. This reduces cyclic adenosine monophosphate (cAMP), activates inwardly rectifying potassium currents, and inhibits voltage-gated Ca²⁺ channels. The result is inhibition and hyperpolarization of excitable membranes.

M₁ receptors, also called neural receptors, are primarily located in the CNS, PNS, and parietal cells. These receptors regulate gastrointestinal secretions following vagal stimulation, learning, motor function, and memory. M₂ receptors, also called cardiac receptors, are majorly located in the heart and regulate negative inotropic and chronotropic effects while simultaneously stimulating smooth muscle contractions. M₃ receptors are abundantly present in the smooth muscles and glands, where their activation stimulates muscle contraction and gland secretion. M₄ and M₅ receptors are located within the CNS and limit transmitter release.