In recent years a unique form of neurotransmitter action has been described which does not result from a transmitter-induced opening of a membrane channel. Rather, it results from a modulation by the transmitter of a channel opened by voltage. A role for this form of neurotransmitter action was first implicated in the positive inotropic and chronotropic effects of nor-adrenaline on cardiac muscle. Since that time, neurotransmitter modulation of voltage-dependent channels has been described for many tissues. In particular, this type of transmitter effect may be involved in presynaptic inhibition of sensory neurotransmission in the spinal cord. This proposal investigates this phenomenon in embryonic chick sensory neurons in vivo and in vitro. Specifically, the mechanism by which neurotransmitters (e.g., GABA and nor-epinephrine) decrease the voltage-dependant Ca current in the cell bodies of the neurons will be investigated using voltage clamp and single channel recording techniques. The experiments are designed to test the involvement of cyclic nucleotides and intracellular Ca in channel modulation and to gain information about their roles in the regulation of neurotransmitter release from sensory neurons. Tests of hypotheses concerning the mechanism of pre-synaptic inhibition will also be performed both in hemisected spinal cord preparations and at identified synapses between sensory neurons and spinal cord cells grown together in culture. These studies will make use of the observation that two pharmacologically and functionally distinct GABA receptors exist on embryonic chick sensory neurons. The specific agonists for these receptors will allow a discrimination between two proposed hypotheses for presynaptic inhibition in the spinal cord.
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