TY - JOUR
T1 - Sensitization of adenylate cyclase by Gαi/o-coupled receptors
AU - Watts, Val J.
AU - Neve, Kim A.
N1 - Funding Information:
This work was supported by US Public Health Service grants MH060397 (V.J.W.) and MH045372 (K.A.N.), the National Alliance for Research on Schizophrenia and Depression (V.J.W.), and the Veterans Health Administration Merit Review and Career Scientist programs (K.A.N.). We thank David M. Allen for assistance with preparation of the figures. We also thank the reviewers of this article for their thoughtful reviews and insightful suggestions. Finally, we acknowledge the outstanding scientists whose work is cited in this review for their contributions to our understanding of G protein-coupled receptor signaling.
PY - 2005/6
Y1 - 2005/6
N2 - Activation of receptors coupled to inhibitory G proteins (Gαi/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 Gαi/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 Gαs-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. Gαi/o-coupled receptor-induced heterologous sensitization may contribute to enhanced Gαs-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.
AB - Activation of receptors coupled to inhibitory G proteins (Gαi/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 Gαi/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 Gαs-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. Gαi/o-coupled receptor-induced heterologous sensitization may contribute to enhanced Gαs-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.
KW - Adenylate cyclase
KW - Drug abuse
KW - G proteins
KW - Heterologous sensitization
KW - Superactivation
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U2 - 10.1016/j.pharmthera.2004.12.005
DO - 10.1016/j.pharmthera.2004.12.005
M3 - Review article
C2 - 15922020
AN - SCOPUS:19444378697
SN - 0163-7258
VL - 106
SP - 405
EP - 421
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 3
ER -