Identification of Ethanol Responsive Domains of Adenylyl Cyclase

Abstract

The current study with mammalian ACs provides a new class of alcohol-responsive protein and possibly a new mechanism of alcohol action on cellular function. The identification of ethanol responsive domains will facilitate the elucidation of the mechanisms by which ethanol enhances the activity of AC.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…In contrast, in the case of ACs, there are relatively few studies on chimeras of full-length AC isoforms (Levin and Reed, 1995;Crossthwaite et al, 2005;Yoshimura et al, 2006;Diel et al, 2008). A major reason for this situation is the fact that the chimeras are unstable and, hence, functionally inactive (Seebacher et al, 2001).…”

“…Starting from the early observation that ethanol at clinically relevant concentrations increases AC activity in mouse striatal membranes (Hoffman and Tabakoff, 1982), subsequent studies revealed that AC7 is particularly sensitive to stimulation by ethanol and that the effects of ethanol are mediated via the cytosolic domains (Yoshimura and Tabakoff, 1999;Yoshimura et al, 2006;Kou and Yoshimura, 2007;Dokphrom et al, 2011). Female mice with reduced AC7 levels show increased alcohol consumption, whereas increased AC7 levels lead to elevated ethanol-induced adrenocorticotropin and corticosterone levels (Pronko et al, 2010;Desrivieres et al, 2011).…”

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

“…But despite decades of investigation, the evidence is inconclusive for any specific molecular target for ethanol on any protein (for reviews see (6,7)). Many potential protein targets have been identified (4,8) including voltage-gated Na þ channels (9), adenylyl cyclase (10,11), guanine nucleotide binding protein G s (12), the GLT1 glutamate transporter (13), gap junctions (14), g-aminobutyric acid (GABA) A receptors (6), n-methyl-daspartate (NMDA) receptors (15), nicotinic acetylcholine receptor (nAChR) channels (16,17), and the cannabinoid receptor 1 (18). One system within the brain that appears to be sensitive to alcohol dependence is the endocannabinoid system (for review see (19)).…”

Regions on Adenylyl Cyclase VII Required for Selective Regulation by the G13Pathway

“…The boundaries of the C1a, C1b, and C2 domains are aa197-aa454, aa455-aa595, and aa864-aa1080, respectively, according to the human AC7 protein (NP_001105.1). The AC7-2C1aN construct was a gift from Dr. Masami Yoshimura (Yoshimura et al, 2006). The constructs containing the NAAIRS (AsnAla-Ala-Ile-Arg-Ser) sequence were generated by site-directed mutagenesis PCR of the targeted regions followed by cloning of the mutated fragments into pFBneo-AC7-myc vector using two unique restriction enzymes.…”

“…3). Replacing the C1 domain of AC7 with that of AC2 resulted in an inactive enzyme (unpublished data; Yoshimura et al, 2006). Replacing the membrane domains of AC7 with those of AC2 yielded a functional cyclase, AC7-2M1-2M2.…”