CARDIAC-SPECIFIC OVEREXPRESSION OF THE L-TYPE VOLTAGE DEPENDENT CALCIUM CHANNEL IN THE MOUSE
Voltage-dependent calcium channels (VDCC’s) mediate the influx of Ca ^2+ in response to membrane depolarization and regulate numerous intracellular pathways including: contraction, secretion, neurotransmitter release, and gene transcription. Calcium is the most ubiquitous signaling molecule, but elicits the most exquisitely specific responses. Therefore, proper regulation and control of Ca ^2+ mobilization is essential to prevent aberrant signaling. Although a large body of knowledge has been accumulated on VDCC’s, physiological characteristics in native tissue and the contribution of the channels to broad scope function remain vague. This study focuses on the cardiac-specific overexpression of the L-VDCC in the mouse which will further the understanding of the in vivo function and role of the L-VDCC in normal and diseased myocardium. In addition, compensatory mechanisms associated with the change in Ca ^2+ homeostasis will be identified. Overexpression of the ?1 subunit (Ca v 1.2) increased Ca ^2+ influx into cardiomycytes, which resulted in an increase in cardiac contractile force. Interestingly, expression of the accessory subunits was unchanged compared to nontransgenic animals. Since no differences were observed in the activation or inactivation kinetics of the channel, the core stoichiometry remains intact between transgenic and nontransgenics. Two major findings in this transgenic model include an early loss of the ? adrenergic receptor signaling pathway and a slow-progressing development of heart failure, both common characteristics of human pathology. Additionally, enhanced PKC ? activation was an early event, which may serve as the common link between disease developmentand the defect in ? adrenergic receptor signaling. Numerous signaling pathways have been identified to be involved in cardiac hypertrophy with no clear common member other than Ca ^2+ . Clearly in this model, the increase ingress of Ca ^2+ initiates the hypertrophic program with associated fibrosis, alterations in gene transcription, and apoptosis, as well as an elevation of PKC ? . Thus, the Ca ^2+ channel overexpression mouse model provides a useful tool to define the prominent intracellular signaling pathways influenced by aberrant Ca ^2+ signaling in heart failure and to emphasize a central role for Ca ^2+ in hypertrophy and failure.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:calcium channel transgenic mice heart disease
Date of Publication:01/01/2001