Auto-inhibition of adenylyl cyclase 9 (AC9) by an isoform-specific motif in the carboxyl-terminal region

Adrienn Pálvölgyi, James Simpson, Ibolya Bodnár, Judit Bíró, Miklós Palkovits, Tamás Radovits, Paul Skehel, Ferenc A. Antoni

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Trans-membrane adenylyl cyclase (tmAC) isoforms show markedly distinct regulatory properties that have not been fully explored. AC9 is highly expressed in vital organs such as the heart and the brain. Here, we report that the isoform-specific carboxyl-terminal domain (C2b) of AC9 inhibits the activation of the enzyme by Gs-coupled receptors (GsCR). In human embryonic kidney cells (HEK293) stably overexpressing AC9, cAMP production by AC9 induced upon the activation of endogenous β-adrenergic and prostanoid GsCRs was barely discernible. Cells expressing AC9 lacking the C2b domain showed a markedly enhanced cAMP response to GsCR. Subsequent studies of the response of AC9 mutants to the activation of GsCR revealed that residues 1268–1276 in the C2b domain were critical for auto-inhibition. Two main species of AC9 of 130 K and ≥ 170 K apparent molecular weight were observed on immunoblots of rodent and human myocardial membranes with NH2-terminally directed anti-AC9 antibodies. The lower molecular weight AC9 band did not react with antibodies directed against the C2b domain. It was the predominant species of AC9 in rodent heart tissue and some of the human samples. There is a single gene for AC9 in vertebrates, moreover, amino acids 957–1353 of the COOH-terminus are encoded by a single exon with no apparent signs of mRNA splicing or editing making it highly unlikely that COOH-terminally truncated AC9 could arise through the processing or editing of mRNA. Thus, deductive reasoning leads to the suggestion that proteolytic cleavage of the C2b auto-inhibitory domain may govern the activation of AC9 by GsCR.

Original languageEnglish
Pages (from-to)266-275
Number of pages10
JournalCellular Signalling
Volume51
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Adenylyl cyclase, cyclic AMP, myocardium
  • Auto-inhibition
  • Heart failure
  • Limited proteolysis

ASJC Scopus subject areas

  • Cell Biology

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