Gαi/o-coupled receptor-mediated sensitization of adenylyl cyclase: 40 years later
Section snippets
Introduction to heterologous sensitization
The history of and basic concepts involving heterologous sensitization of adenylyl cyclase were extensively discussed in our previous review (Watts and Neve, 2005). Thus, the present review will provide a limited introduction describing the history of this topic, and then incorporate recent findings into our current understanding of this paradoxical phenomenon, first described forty years ago in the laboratory of Dr. Marshall Nirenberg (Sharma et al., 1975).
G protein-coupled receptors (GPCRs)
Gαi/o subunits
Heterologous sensitization is a phenomenon shared by numerous Gαi/o-coupled receptors and, because of this, is linked to activation of Gαi/o proteins. Mechanistically, inactivation of Gαi/o with pertussis toxin treatment blunts receptor-mediated heterologous sensitization (Watts, 2002). Pretreatment with pertussis toxin leads to ADP-ribosylation of Gαi/o subunits, ultimately preventing their activation by receptors. Because pertussis toxin inhibits all isoforms of Gαi (i.e. Gαi1, Gαi2, Gαi3),
Heterologous sensitization in animals
Demonstration in animal models was an important step in the establishment of heterologous sensitization as a more physiologically relevant receptor response following prolonged activation of Gαi/o-coupled receptors. For example, in 1988 Nestler and Tallman observed that following a five-day chronic treatment of rats with subcutaneous morphine pellets, there was an increase in the amounts of active PKA in the locus coeruleus. These results are consistent with the known outcomes of heterologous
Conclusions and future perspectives
Heterologous sensitization is characterized by a seemingly paradoxical increase in the activity of adenylyl cyclases following prolonged activation of Gαi/o-coupled receptors. Increasing evidence suggests that several proteins are involved in the development and expression of heterologous sensitization of adenylyl cyclase isoforms. Moreover, there appear to be adenylyl cyclase-isoform specific mechanisms. The reports discussed here suggest that during persistent activation of Gαi/o-coupled
Disclosures
The authors have no conflicts of interest to disclose. This work was supported by the National Institute of Mental Health [Grants MH060397 and MH101673], the Purdue Research Foundation, and by Purdue University.
Acknowledgments
The authors wish to acknowledge Ms. Isabelle Verona Brust for preparing the figures in the manuscript and Ms. Stacy O. Nall for editorial assistance.
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