Many neurotransmitters act by opening or closing ionic channels in the membranes of target cells. Transmitter control of channels is the fundamental mechanism underlying synaptic transmission between neurons, as well as the control of the heart and other organs by the nervous system. The long-term goal of the proposed research is to use an electrophysiological approach to understand the mechanisms by which transmitters control the operation of ionic channels. In particular, the work will focus on understanding how neurotransmitters modulate voltage-dependent calcium-selective channels in vertebrate heart muscle and neurons. Patch clamp techniques will be used to investigate transmitter control of calcium channels in cardiac muscle, sensory and sympathetic neurons, hippocampal neurons, dopaminergic neurons, and cerebellar Purkinje neurons. The mechanism of channel control by transmitters and hormones such as adrenaline, norepinephrine, GABA, glutamate, adenosine, and opioid peptides will be studied at the level of the single cell and the single channel. This approach will help answer basic questions about several related transmitter mechanisms. Does adrenaline increase cardiac calcium current by altering voltage-dependent gating? Is transmitter inhibition of calcium channels in sympathetic neurons mediated by direct binding of GTP-binding proteins? What second messenger systems mediate glutamate inhibition of calcium channels in central neurons? Which types of calcium channels are controlled by glutamate, GABA, adenosine, and opiates in central neurons? Are P-type calcium channels in Purkinje neurons modulated by transmitters? Neurotransmitter control of calcium channels is a basic process for the normal operation of the brain and the cardiovascular system. Understanding the mechanisms involved will help understand pathological states such as cardiac arrhythmias, cardiac failure, stroke, and epilepsy.
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