title: Novel function of α1DL-type calcium channel in the atria.
abstract: Ca entry through atrial L-type Calcium channels (α1Cand α1D) play an important role in muscular contraction, regulation of gene expression, and release of hormones including atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP). α1DCa channel is exclusively expressed in atria, and has been shown to play a key role in the pathogenesis of atrial fibrillation. Recent data have shown that the small conductance calcium-activated potassium channel, SK4 is also atrial specific and also contributes prominently to the secretion of ANP and BNP. However, its functional role in the heart is still poorly understood. Here we used α1Dgene heterozygous (α1D+/-) mice and HL-1 cells to determine the functional contribution of SK4 channels to α1D-dependent regulation of ANP and BNP secretion in response to endothelin (ET), and/or mechanical stretch. Immunoprecipitation with α1Dspecific antibody and western blotting with SK4 specific antibody on the immuno-precipitated protein complex showed a band at 50 KDa confirming the presence of SK4 in the complex and provided evidence of interaction between SK4 and α1Dchannels. Using RT-PCR, we observed a 2.9 fold decrease in expression of Cacna1d (gene encoding α1D) mRNA in atria from α1D+/-mice. The decrease in α1DmRNA corresponded with a 4.2 fold decrease in Kcnn4 (gene encoding SK4) mRNA from α1D+/-mice. These changes were paralleled with a 77% decrease in BNP serum levels from α1D+/-mice. When α1Dwas knocked down in HL-1cardiomyocytes using CRISPR/Cas9 technology, a 97% decrease in secreted BNP was observed even in cells subjected to stretch and endothelin. In conclusion, our data are first to show that α1DCa and SK4 channels are coupled in the atria, and that deletion of α1Dleads to decreased SK4 mRNA and BNP secretion providing evidence for a novel role of α1Din atrial endocrine function. Elucidating the regulatory factors that underlie the secretory function of atria will identify novel therapeutic targets for treatment and prevention of cardiac arrhythmias such as atrial fibrillation.
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Ujala
authors.initials: U
authors.lastname: Srivastava
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Ademuyiwa S
authors.initials: AS
authors.lastname: Aromolaran
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Fabris
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Deana
authors.initials: D
authors.lastname: Lazaro
authors.affiliation: State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kassotis
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare System and Departments of Medicine, Cell Biology and Pharmacology, USA; State University of New York Downstate Medical Center, Brooklyn, NY, USA; Department of Medicine, New York University School of Medicine, New York, NY, USA. Electronic address: mohamed.boutjdir@va.gov.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism; D064113:CRISPR-Cas Systems; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism*; D006579:Heterozygote; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain
keywords: Alpha(1D) calcium channel; Atria; Atrial fibrillation; Brain natriuretic peptide