SREBP Positively Regulates the Parasympathetic Response of the Heart

The response of the heart to parasympathetic control involves stimulation of an acetylcholine sensitive current, IKAch, via activation of a G protein-coupled inward rectifying K channel, GIRK1/GIRK4. In an in vitro model for lipid lowering, embryonic chick atrial myocytes (EAM) cultured in absence of lipoproteins (LPDS) demonstrated both a markedly increased negative chronotropic response to parasympathetic stimulation and an increased level of the lipid-sensitive transcription factor, sterol response element binding protein (SREBP). Here we show that compared to cells cultured in FBS, growth of EAM in LPDS increased both the expression of GIRK1 protein and GIRK1 promoter activity. Overexpression of SREBP1a and 1c, but not SREBP2 mimicked the effect of LPDS on GIRK1 promoter activity and protein level. Analysis of deletion constructs and site-specific mutations of the GIRK1 promoter identified a regulatory complex consisting of an E-box and 2 tandem sterol response elements required for regulation by LPDS and/or SREBP. EAM cultured in LPDS demonstrated a 3 fold increased carbamylcholine-stimulated IKAch compared to cells grown in FBS. Expression of DN-SREBP reversed the effect of on GIRK1 promoter activity, GIRK1 protein level and IKAch. These data demonstrate a novel relationship between lipid metabolism and the regulation of the parasympathetic response of the heart.