Abstract 2571: Compensatory Responses to Heterozygous Conditional Knockout of the Cav1.2 Gene in Mouse Heart
Expression of the L-type voltage-gated calcium (Ca2+) channel appears to be under tight regulatory control and channel expression levels are more stable in a variety of pathological conditions than is found for most other ion channels. This may reflect the critical role of the channel in cardiac physiology as the primary link between myocardial electrical excitation and contraction. In the ventricles of most mammals, including humans, the principal subunit of the L-type Ca2+ channel is encoded by the Cav1.2 (CACNA1C) gene. We have studied how the myocardium responds to perturbations affecting Ca2+ channel gene dosage in order to understand the regulatory mechanisms controlling its expression. We used cardiac-specific inducible (αMHC-MER-Cre-MER) Cav1.2 knockout mice to address this issue. After induction of gene deletion using tamoxifen, homozygote knockout mice died rapidly (6.9±3 days). Echocardiographic analysis showed that myocardial contractility was reduced to 14±1% of control values shortly before death. In these mice, Cav1.2 mRNA was reduced to 11±1% (P<0.0001) of control values, consistent with an almost complete knockout of the Cav1.2 gene, and Cav1.2 protein was reduced to 19±9 % (P<0.0001). In contrast, heterozygous conditional knockout mice survived following tamoxifen induction, and their echocardiographic parameters did not show significant changes compared to control mice. Cav1.2 mRNA expression in the left ventricle of heterozygous knockout mice was reduced to about 58±3% (P<0.0001) of control values. However, there was only a 21±2% (P<0.0001) reduction in Cav1.2 protein expression compared to control mice. There was no change in the L-type Ca2+ current density. The biophysical properties of the current, as measured by whole-cell voltage clamp, were also unchanged. In conclusion, these results indicate the presence of one or more post-transcriptional mechanisms that stabilize or otherwise buffer expression of L-type Ca2+ current in cardiac ventricular myocytes following deletion of one Cav1.2 allele. Understanding these mechanisms will provide insights into the pathophysiology of cardiac diseases in which changes in L-type Ca2+ channel current have been identified, including heart failure and atrial fibrillation.