Perspectives in Pharmacology Molecular Mechanisms for Heterologous Sensitization of Adenylate Cyclase VAL J. WATTS Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana Received March 18, 2002; accepted April 17, 2002 This article is available online at http://jpet.aspetjournals.org ABSTRACT The nine membrane-bound isoforms of the enzyme adenylate cy- clase (EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting through G protein-coupled receptors to modulate intra- cellular cAMP levels. In general, acute activation of G s -coupled receptors stimulates cAMP accumulation, whereas acute activation of G i/o -coupled receptors typically inhibits cAMP accumulation. It is also well established that persistent activation of G-protein coupled receptors will alter subsequent drug-modulated cAMP accumulation. These alterations are thought to represent cellular adaptive re- sponses following prolonged receptor activation. One phenomenon commonly observed, heterologous sensitization of adenylate cy- clase, is characterized by an enhanced responsiveness to drug- stimulated cAMP accumulation following persistent activation of G i/o -coupled receptors. Heterologous sensitization of adenylate cy- clase was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory receptors. Such an adaptive mechanism has been suggested to play a role in the processes of addiction to and withdrawal from many drugs of abuse and in psychiatric disorders including schizophrenia and de- pression. Although the precise mechanisms remain unknown, re- search over the last decade has led to advances toward understand- ing the molecular events associated with heterologous sensitization of recombinant and endogenous adenylate cyclases in cellular mod- els. These events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified G s -dependent events that are involved in the expression of heterologous sensitization. Historical Perspective Acute activation of G i/o -coupled receptors inhibits cAMP accumulation, whereas prolonged activation enhances drug- stimulated cAMP accumulation. This enhanced responsive- ness was first observed following persistent activation of the -opioid receptor in the laboratory of Dr. Marshall Nirenberg (National Institute of Mental Health, Bethesda, MD), who proposed that the increased responsiveness was a mecha- nism of opiate tolerance and dependence (Sharma et al., 1975). This phenomenon has since been described using many different names, including cAMP overshoot, supersen- sitivity, superactivation, supersensitization, and heterolo- gous sensitization of adenylate cyclase (EC 4.6.1.1). 1 The term heterologous sensitization will be used throughout this article to describe observations where persistent activation of aG i/o -coupled receptor induces an enhanced response to drug-stimulated cAMP accumulation (Fig. 1). Those initial observations from the Nirenberg laboratory (Sharma et al., 1975) prompted a number of subsequent investigations aimed at determining the receptor and tissue specificity of heterologous sensitization and identifying the molecular mechanisms responsible for this phenomenon. These studies revealed that persistent activation of several G i/o -coupled receptors (including opioid,  2 -adrenergic, adenosine, soma- tostatin, and muscarinic receptors) induces heterologous sen- sitization in both neuronal and non-neuronal cellular models (see review by Thomas and Hoffman, 1987). Based on the results from these studies, Thomas and Hoffman (1987) pro- posed the following model: chronic agonist stimulation of a G i -coupled receptor induces heterologous sensitization through a pertussis toxin-sensitive G protein, invoking an unknown mechanism that may ultimately alter G s ,G i , or adenylate cyclase to contribute to the enhanced cAMP re- sponse. Furthermore, this mechanism does not involve de- sensitization or tolerance of the G i -coupled receptor, and the This work was supported by the National Institute of Mental Health, MH60397, the National Alliance for Research on Schizophrenia and Depres- sion, and Purdue University. 1 I have used adenylate cyclase as the common name of the enzyme EC 4.6.1.1 based on the recommendation of the International Union of Biochem- istry and Molecular Biology (IUBMB) (http://www.chem.qmw.ac.uk/iubmb/en- zyme/EC4/6/1/1.html). Other sources that list adenylate cyclase as the pre- ferred common name include Dorland’s Medical Dictionary, the Sourcebook of Enzymes by White and White, Stedman’s Medical Dictionary (27th edition), and the Oxford Dictionary of Biochemistry and Molecular Biology. ABBREVIATIONS: AC, adenylate cyclase; PKA, cAMP dependent protein kinase A. 0022-3565/02/3021-1–7$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 302, No. 1 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 35105/995628 JPET 302:1–7, 2002 Printed in U.S.A. 1 at ASPET Journals on November 13, 2017 jpet.aspetjournals.org Downloaded from