G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.

The G-protein or guanine nucleotide-binding protein, is a large heterotrimeric complex. Its three subunits are labeled alpha (α), beta (β), and gamma (γ). When the receptor is unbound or resting, the α-subunit binds a guanosine diphosphate molecule or GDP, and all three subunits are attached to the receptor.

When a ligand binds the receptor, the α-subunit releases the GDP and binds a molecule of guanosine triphosphate (GTP). This action releases the α-GTP complex and the β-γ complex from the receptor. The α-GTP can move along the membrane to activate second messenger pathways such as cAMP. However there are different types of α-subunits and some are inhibitory, turning off cAMP.

The β-γ complex may interact with potassium ion channels which release potassium (K+) into the extracellular space resulting in hyperpolarization of the cell membrane. This type of ligand-gated ion channel is called a G-protein coupled inwardly rectifying potassium channel or GIRK.

Ligands do not permanently bind the receptor. When the ligand leaves the receptor, it becomes available for the G-protein units to recouple and reattach. Before this though, nearby enzymes must hydrolyze the GTP attached to the α-subunit back into GDP. Once this is achieved, the β-γ complex reassembles with the GDP-α complex, and the whole G-protein reattaches to its receptor domain.

Common G-protein coupled receptors are: muscarinic acetylcholine receptors found in skeletal muscles, Beta-1 adrenergic receptors in the heart, and vasopressin receptors on smooth muscle cells. In sensory systems, like olfactory receptors and some taste receptors, the binding ligands are environmental molecules. For example, sucrose molecules bind G-protein coupled receptors resulting in the perception of sweet taste.

Alterations in G-protein coupled receptors may play a substantial role in mood disorders, like depression. Serotonin is a ligand for the 5HT1A receptor, a G-protein coupled receptor. It has been suggested that, in depression, interactions between the ligand and the receptor are changed; either the ligand does not bind long enough or the receptor does not fully respond. This results in poor serotonergic signaling which manifests as depression.