L-type calcium channel gating and modulation in normal and failure states

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Functional hallmarks of heart failure include prolonged action-potential duration, depressed contraction and intracellular Ca2+ transients, as well as blunted adrenergic responsiveness. Among the molecules implicated as underlying players, the L-type channel is particularly important. For example, in cells isolated from dogs with pacing-induced heart failure (HF cells), a key factor underlying action potential prolongation appears to be decreased L-type channel inactivation. However, rigorous assessment of the role of L-type channels in heart failure is hampered by crucial gaps in understanding inactivation and functional modulation by auxiliary channel subunits. The overall goal is to deepen fundamental understanding of L-type channels in these gap areas, and to bridge the enhance basic knowledge to a new appreciation of how these channels contribute to heart failure. Using HF cells from dogs and humans, we will pursue the following 5 Aims, each targeting a salient gap in understanding channel performance during failure. 1. To clarify fundamental uncertainties about voltage-dependent inactivation of cardiac L-type channels. 2. To discover structure-based mechanisms of Ca2+- dependent inactivation of cardiac L-type channels. 3. To determine the potential for tuning L-type channel function and expression by Ca channel beta subunits. 4. To identify the profile of Ca channel beta subunits in normal and failing dog and human heart tissue. 5. To establish a functional profile of L-type channel properties in HF cells., and to test whether expression of recombinant beta subunits can alter or "normalize" identified irregularities in function. The latter experiments will help lay the groundwork for gene therapy of excitability disorders and heart failure.