GPCRs play a critical role in developmental processes and synaptic transmission in the central nervous system (CNS), as well as in learning and memory, thought and emotional state, motor and hormonal control, and pain sensation. Analysis of the human genome sequence revealed a repertoire of 367 nonsensory GPCRs for endogenous ligands,1 over 100 of which remain "orphan receptors" without known naturally occurring ligands. Expression profiling predicts that an unexpectedly large number (over 90%) of nonsensory GPCRs are found in the brain, each with a unique distribution pattern and a high degree of overlap, producing thousands of distinct cell-specific combinations.

Additional sequence variation is generated in the CNS through receptor polymorphisms, alternative splicing, and RNA editing, and receptor function is regulated by a wide array of post-translational modifications including glycosylation and phosphorylation. This chapter profiles several prominent GPCR families in the CNS area with respect to structure and function, with an intentional focus on receptors of relevance to modern drug discovery.

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