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Vol. 302, Issue 1, 1-7, July 2002
Department of Medicinal Chemistry and Molecular Pharmacology,
Purdue University, West Lafayette, Indiana
The nine membrane-bound isoforms of the enzyme adenylate cyclase
(EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting
through G protein-coupled receptors to modulate intracellular cAMP
levels. In general, acute activation of G
s-coupled receptors stimulates cAMP accumulation, whereas acute activation of
Gi/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 responses following prolonged receptor activation. One
phenomenon commonly observed, heterologous sensitization of adenylate
cyclase, is characterized by an enhanced responsiveness to
drug-stimulated cAMP accumulation following persistent activation
of Gi/o-coupled receptors. Heterologous
sensitization of adenylate cyclase 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
depression. Although the precise mechanisms remain unknown, research
over the last decade has led to advances toward understanding the
molecular events associated with heterologous sensitization of
recombinant and endogenous adenylate cyclases in cellular models. These
events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified Gs-dependent events that are
involved in the expression of heterologous sensitization.
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