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7256413 
Journal Article 
Neuroendocrine GPCR Signaling 
Millar, RP; Newton, CL; Roseweir, AK; , 
2012 
ELSEVIER ACADEMIC PRESS INC 
SAN DIEGO 
HANDBOOK OF NEUROENDOCRINOLOGY 
21-53 
WOS:000321820500003 
G-protein coupled receptors (GPCRs) mediate the majority of neuroendocrine signaling and are the major targets of current neuroendocrine therapeutics. Currently, the major neuroendocrine GPCR families are the rhodopsin, secretin and glutamate families. Most neuroendocrine ligands are neuropeptides, but lipid molecules and biogenic amines are also important regulators. Upon ligand binding of the cognate GPCR, they undergo conformational change into an active state which facilitates binding of a heterotrimeric G protein comprised of alpha, beta and gamma subunits. This leads to activation of the G protein and the displacement of GDP bound to the alpha subunit by GTP. This results in dissociation of the alpha subunit from the beta gamma subunits, and activation or inhibition of intracellular effectors resulting in downstream signaling cascades which alter cellular activity and gene expression. There are four major classes of G proteins; G(s), which activates adenylate cyclase to generate cAMP, which then activates protein kinase A; G(i/o), which inhibits adenylate cyclase; G(q/11), which activates phospholipase C beta to generate inositol trisphospate (which mobilizes intracellular Ca2+) and diacyl glycerol (which activates protein kinase C); and G(12/13), whose targets are less well defined. There is a wide range of isoforms for each of the subunits, such that there is potentially a large number of combinations making up the heterotrimeric G proteins. While the G alpha subunits are largely responsible for the activation or inhibition of the effector enzymes, the G beta gamma is also able to alter cellular systems such as ion channels. Hydrolysis of GTP to GTP on the alpha subunit allows it to reassociate with the beta gamma subunits so that the heterotrimeric G protein is available for another cycle of GPCR activation. GPCRs have been shown recently to also activate or recruit non-G proteins such as beta-arrestin to initiate cellular events. Selectivity of GPCRs for signaling pathways and/or desensitization may be modified by phosphorylation by kinases, homo- or hetero-dimerization or oligomerization, and by association with a host of intracellular proteins. In addition, these elements may modify the selectivity of the GPCR for ligands. GPCR activities may also be modulated by proteins that affect their expression and trafficking to the cell surface. Taken together, there is a vast array of mechanisms that can affect GPCR signaling, which is influenced by the cellular context and numerous inputs on cellular function. In addition to being major targets for development of therapeutics, dysfunction of GPCRs, G proteins and effectors through mutation leads to many disease states. 
Fink, G; Pfaff, DW; Levine, JE; 
978-0-12-375097-6