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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Novel function of α1D L-type calcium channel in the atria
Ujala Srivastava1, Ademuyiwa S Aromolaran1, Frank Fabris1
1Cardiovascular 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.
Insights
The atrial L-type calcium channel alpha1D (α1D) interacts with the SK4 channel, regulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) secretion. Deleting α1D reduces SK4 expression and BNP release, suggesting a novel role in atrial endocrine function and potential therapeutic targets for arrhythmias.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Atrial L-type Calcium channels (α1C and α1D) regulate cardiac functions, including hormone release (ANP, BNP).
- The α1D Ca channel is atrial-specific and implicated in atrial fibrillation pathogenesis.
- The small conductance calcium-activated potassium channel, SK4, is also atrial-specific and involved in ANP/BNP secretion, but its cardiac role is unclear.
Purpose of the Study:
- To investigate the functional interaction between SK4 channels and α1D Ca channels.
- To determine the role of SK4 in α1D-dependent ANP and BNP secretion.
- To explore the impact of α1D deletion on SK4 expression and atrial hormone secretion.
Main Methods:
- Utilized α1D gene heterozygous (α1D+/-) mice and HL-1 cardiomyocytes.
- Performed immunoprecipitation and western blotting to confirm α1D-SK4 interaction.
- Employed RT-PCR to assess gene expression (Cacna1d, Kcnn4).
- Measured BNP serum levels and secretion in response to endothelin and mechanical stretch.
Main Results:
- Confirmed physical interaction between α1D and SK4 channels.
- Observed decreased α1D and SK4 mRNA expression in α1D+/- mice.
- Documented a significant reduction in BNP serum levels in α1D+/- mice.
- Demonstrated a substantial decrease in BNP secretion in α1D-knockdown HL-1 cells.
Conclusions:
- α1D Ca and SK4 channels are physically coupled in atrial cells.
- α1D channel deletion leads to reduced SK4 expression and atrial natriuretic peptide secretion.
- This study reveals a novel role for α1D in atrial endocrine function, identifying potential therapeutic targets for cardiac arrhythmias like atrial fibrillation.
Abstract:
Ca entry through atrial L-type Calcium channels (α1C and 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). α1D Ca 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 α1D gene 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 α1D specific 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 α1D channels. 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 α1D mRNA 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 α1D was 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 α1D Ca and SK4 channels are coupled in the atria, and that deletion of α1D leads to decreased SK4 mRNA and BNP secretion providing evidence for a novel role of α1D in 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.
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