The neurotransmitter gamma-aninobutyric acid (GABA) can act on either GABA/A or GABA/B recognition sites. The molecular events related to the activateion fo GABA/A sites are well known and relate to these sites being part of a chloride channel. In contrast to the GABA/A site, the GABA/B site is reported to couple to at least four different transducing systems. One of these transducers is the inhibitory adenylate cyclase. The physiological significance of a GABA/B receptor can only be elucidated by the responses elicited from GAVA/B agonists. Fortunately, the GABA analog, baclofen, is a selective GABA/B agonist. Baclofen is therapeutic for spasticity seen in individuals with spinal cord injury or having multiple sclerosis. Baclofen is believed to inhibit the reflex loops in the spinal cord. The mechanism of action and the transducing systems involved in producting this therapeutic action is unknown. However, baclofen is known to inhibit the release of excitatory transmitter in spinal cord. It is possible that baclofen inhibits the release of transmitter from a nerve terminal in the spinal reflex loop to produce its antispastic action. However, the transducing system that is involved in the GABA/B receptor mediated inhibition of transmitter release is again unknown. In this grant application, the mechanism of those GABA/B receptors that inhibit adenylate cyclase and attenuate the release of trasmitter will studied. The working hypothesis that will be tested in this grant is that GABA/B receptors, by lowering the cyclic AMP content, prevent protein kinase A from phosphorylating the dihydropyridine (DHP) sensitive voltage dependent calcium cannel (VDCC). The DHP- VDCC is reportedly able to conduct calcium only after it is phosphorylated. When this occurs, calcium entry into the cell is enchanced and more transmitter is released. If GABA/B receptors lower cyclic AMP content by inhibiting adenylate cyclas, less calcium will enter with cell depolarization because the DHP- VDCCs are not phosphorylated and cannot conduct calcium. Less transmitter is thereby released. The proposed studies will be performed on a nearly homogenous population of one nerve cell type in primary culture. The understanding of the GABA/B transmembrane signaling mechanism may lead to a rational treatment of pathological states such as spasticity, some forms of epilepsy, and other neuropsychiatric conditions which involve an increased transmission at excitatory synapses that are presynaptically modulated by GABA/B receptors.
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