Many neurotransmitters act by opening or closing ionic channels in the membranes of target cells. Transmitter control of channels is a fundamental mechanism underlying the regulation of the heart and other organs by the nervous system, as well as for synaptic transmission between nerve cells. The mechanisms by which transmitters control channels are poorly understood; in most cases, the link between transmitter binding and channel control seems less direct than for the end-plate acetylcholine receptor, where the channel is tightly coupled to the receptor. The long term-goal of the proposed research is to use an electrophysiological approach to understand the range of mechanisms by which transmitters control the operation of ionic channels. Of special interest are cases in which transmitter- channel coupling may be indirect, including transmitter modulation of voltage-dependent channels. Transmitter control of channels will be investigated in heart muscle, smooth muscle, and neurons from frogs, rats, and rabbits. Patch clamp techniques will be used to record ionic currents, both at the level of the whole cell and the single channel, using single cells dispersed from tissue or grown in culture. The approach will help answer basic questions about several related transmitter mechanisms. Do beta-adrenergic agonists increase cardiac calcium current by shifting the voltage- dependence of the channels? Is alpha-adrenergic depression of calcium current in sensory neurons due to a change in the voltage- dependent operation of the channels or to elimination of a fraction of the channels? What channels underlie the hyperpolarization of nerve cells produced by norepinephrine? What channels does external ATP open to produce excitation in heart cells, smooth muscle cells, and neurons? What channels in central neurons are controlled by glutamate, acetylcholine, and norepinephrine? Neurotransmitter control of ionic channels is a basic process for the normal operation of the brain, the heart, and the vascular system. Understanding the mechanisms involved will help understand pathological states such as cardiac arrhythmias, hypertension, epilepsy, depression, and chronic pain.
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