Structure-activity relationships of G protein-coupled receptors

The primary function of cell-surface receptors is to discriminate the speci fic signaling molecule or ligand fi oma large array of chemically diverse e xtracellular substances and to activate an effector signaling cascade that triggers an intracellular response and eventually a biological effect. G pr otein-coupled cell-surface receptors (GPCRs) mediate their intracellular ac tions through the activation of guanine nucleotide-binding signal-transduci ng proteins (G proteins), which form a diverse family of regulatory GTPases that, in the GTP-bound state, bind and activate downstream membrane-locali zed effecters, Hundreds of GPCRs signal through one or more of these G prot eins in response to a large variety of stimuli including photons, neurotran smitters, and hormones of variable molecular structure, The mechanisms by w hich these ligands provoke activation of the receptor/G-protein system are highly complex and multifactorial. Knowledge and mapping of the structural determinants and requirements for optimal GPCR function are of paramount im portance, not only for a better and more detailed understanding of the mole cular basis of ligand action and receptor function in normal and abnormal c onditions, but also for a rational design of early diagnostic and therapeut ic tools that may allow exogenous regulation of receptor and G protein func tion in disease processes, (C) 2000 IMSS. Published by Elsevier Science Inc .