The long-term goal is to determine mechanisms leading to failure of an action potential to activate all of the axonal targets. In pursuit of this goal, regulation of calcium current flowing in motor-nerve terminals in response to depolarization by an action potential will be analyzed. Exogenous ATP and adenosine cause nerve-terminal calcium currents to decrease. Nonhydrolyzable analogues of ATP will be tested to determine whether ATP must first be converted to adenosine to reduce calcium current. Pertussis toxin, cAMP analogues, and phorbol esters will be used to ascertain whether second messengers are involved. The effects of adenosine will be tested in the presence of extracellular Ba2+ to determine whether a decreased calcium current is secondary to adenosine activation of a K+ current. ACh also causes nerve-terminal calcium currents to decrease. Whether this involves nicotinic or muscarinic receptors will be tested. The roles of second messengers and activation of K+ currents will also be analyzed. The calcium current duration becomes shorter as stimulation frequency increases. Whether this is due to inhibition resulting from accumulated extracellular adenosine will be tested. Calcium-dependent calcium channel inactivation will be tested by measuring the relationship between calcium current duration and extracellular calcium, the effects of equimolar substitution of Ba2+ or Sr2+ for calcium, and the time course of recovery-rich membrane patches or immobilized antibodies as probes, ACh, ATP, and calcitonin gene-related peptide (CGRP) release will be measured as the calcium-current duration is varied. A postsynaptic counterpart to presynaptic inhibition of synaptic activation, namely rapid desensitization of glutamate receptors on motoneuron cell bodies, will be characterized by measuring voltage and agonist dose dependence, sensitivity to exogenous glutamate levels, and recovery times using patch-clamp techniques. these and previous studies have utilized embryonic cells. Similar experiments will use motoneurons from adult tissue to determine whether rapid desensitization changes during development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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University of Wisconsin Madison
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Temkin, R; Lowe, D; Jensen, P et al. (1997) Expression of glutamate receptor subunits in alpha-motoneurons. Brain Res Mol Brain Res 52:38-45
Lowe, D L; Jahn, K; Smith, D O (1997) Glutamate receptor editing in the mammalian hippocampus and avian neurons. Brain Res Mol Brain Res 48:37-44
Hatt, H; Schmidt, K F; Smith, D O (1995) Dopaminergic modulation of glutamate-activated channels in the central nervous system. J Neural Transm Suppl 46:77-86
Smith, D O; Lowe, D; Temkin, R et al. (1995) Dopamine enhances glutamate-activated currents in spinal motoneurons. J Neurosci 15:3905-12
Hatt, H; Rosenheimer, J L; Smith, D O (1995) Proton-activated currents in chick spinal motoneurons. J Comp Physiol A 177:503-10
Smith, D O; Conklin, M W; Jensen, P J et al. (1995) Decreased calcium currents in motor nerve terminals of mice with Lambert-Eaton myasthenic syndrome. J Physiol 487 ( Pt 1):115-23
Hamilton, B R; Smith, D O (1992) Calcium currents in rat motor nerve terminals. Brain Res 584:123-31
Smith, D O (1992) Routes of acetylcholine leakage from cytosolic and vesicular compartments of rat motor nerve terminals. Neurosci Lett 135:5-9
Smith, D O; Franke, C; Rosenheimer, J L et al. (1991) Glutamate-activated channels in adult rat ventral spinal cord cells. J Neurophysiol 66:369-78
Smith, D O; Franke, C; Rosenheimer, J L et al. (1991) Desensitization and resensitization rates of glutamate-activated channels may regulate motoneuron excitability. J Neurophysiol 66:1166-75

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