Sensitization of adenylate cyclase by Galpha i/o-coupled receptors.
Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. This heterologous sensitization of cyclic AMP signaling, also called superactivation or supersensitization, likely represents a cellular adaptive response, a mechanism by which the cell compensates for chronic inhibitory input. Recent advances in our knowledge of G protein-mediated signaling, regulation of adenylate cyclase, and other cellular signaling mechanisms have extensively increased our insight into the mechanisms and significance of this phenomenon. In particular, recent evidence points to the Galpha(s)-adenylate cyclase interface as a locus for the expression of the sensitized adenylate cyclase response, and to isoform-specific phosphorylation of adenylate cyclase as one mechanism that can produce sensitization. Galpha i/o-coupled receptor-induced heterologous sensitization may contribute to enhanced Galpha(s)-coupled receptor signaling following neurotransmitter elevations induced by the administration of drugs of abuse and during other types of neuronal function or dysfunction. This review will focus on recent advances in our understanding of signaling pathways that are involved in sensitization and describe the potential role of sensitization in neuronal function.
Watts
Val J
VJ
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. wattsv@pharmacy.purdue.edu
Neve
Kim A
KA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases