The Protein Acyl Transferase ZDHHC21 Modulates ?1 Adrenergic Receptor Function and Regulates Hemodynamics.

ABSTRACT: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233?).Physiological studies of isolated aortae and mesenteric arteries from F233? mice revealed an unexpected defect in responsiveness to phenylephrine, an ?1 adrenergic receptor agonist. In vivo, F233? mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular ?1 adrenergic receptor gene expression. Telemetry studies showed that the F233? mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the ?1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21.Together, the data support a model in which ZDHHC21 F233? diminishes the function of vascular ?1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.

SUBMITTER: Marin EP 

PROVIDER: S-EPMC4984414 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature