L-proline (Pro) could be a possible neuromodulator as suggested by regional differences in its: (a) distribution; (b) high-affinity synaptosomal uptake; (c) K+-induced, Ca+2-dependent release; (d) depolarizing effects on discrete neuronal populations; and (e) high affinity binding to synaptosomal membranes. Interactions between Pro and glutamate have been suggested especially with N-methyl-D-aspartate receptor. Int he spinal core, the depolarizing responses to Pro can be blocked (60-70%) by AP-5 (2- amino-5-phosphono-pentanoic acid) a NMDA competitive antagonist. L- proline-induced depolarizations of CA1 pyramidal cells are blocked by D-AP- 5, Mg2+, and Zn2+). Similarly, 3H-Pro binding in hippocampal membranes is inhibited (=60%) by AP-7 (2-amino-5-phosphono-heptanoic acid, =AP-5). Clinically, high levels of Pro result in varying degrees of neurological impairments ranging from modest, if any, (prolinemia type I) to marked (prolinemia type II) CNS deficits.
The specific aims of this proposal are: (1) To further establish the specificity of 3H-Pro binding to brain synaptic membranes; (2) To unravel the L-Pro-glutamate interaction(s) and physiological relevance; (3) To identify the cell population(s) in the rat brain responsible for specific 3H-Pro binding; and (4) To provide students with the knowledge pertinent to Neurochemistry and Neuropharmacology. These objectives will be accomplished by: (a) performing SAR (structure- activity) studies; (b) probing whether L-Pro interferes with established NMDA responses such as, Ach release from striatal slices or cGMP increases in cerebellum; and (c) receptor and uptake autoradiography experiments. These experiments shall provide evidence for/against the neurotransmitter role of proline, as well as, for working hypotheses on the mechanism(s) that may be involved in the prolinemias. On the other hand, clarification of the NMDA-Pro interaction(s) may be important in our understanding of the parameters germain to NMDA-mediated processes such as ocular dominance columns, or certain types of epilepsy.
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