Voltage-dependent calcium channels are present in all nerve and muscle cells. In heart muscle, calcium entry through voltage- dependent calcium channels triggers contraction. In neurons, calcium entry through presynaptic calcium channels plays multiple roles, including triggering release of neurotransmitter. Calcium channels in cardiac muscle and neurons can be modulated by the action of neurotransmitters and hormones. The proposed work will investigate mechanisms by which neurotransmitters modulate voltage- dependent calcium channels in cardiac myocytes and in hippocampal neurons. Patch clamp techniques will be used to study the control of calcium channels in cardiac myocytes by beta-adrenergic stimulation, using coordinated measurements of whole cell current, gating current, and single channel current. Cloned calcium channels in heterologous expression systems will be used to explore in detail how voltage-dependent gating steps are controlled by phosphorylation of the channel. The control of calcium channels by beta-adrenergic stimulation will be also studied in hippocampal CA3 and granule neurons. The types of calcium channels subject to beta- adrenergic modulation will be identified using selective toxins. The alteration of voltage-dependent gating properties of the channels will be characterized, and the consequences for control of the firing properties of the neurons will be explored. Using cardiac muscle, hippocampal neurons, and cloned channels, the mechanisms underlying potentiated channel activity induced by strong depolarizations will be studied. The physiological significance of this potentiation during action potentials in cardiac muscle and neurons will be evaluated. Neurotransmitter control of calcium channels is a basic process for the normal operation of the heart and the brain. Understanding the mechanisms involved will help understand pathological states such as cardiac arrhythmias, cardiac failure, stroke, and epilepsy.
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