The underlying mechanism(s) of neurological signs caused by heavy metals have been correlated to alterations in cholinergic, adrenergic and gabaergic transmission leading to impairment of neural transmission. It is well established that hormones, neurotransmitters (NTs) and other biologically active substances interact with their selective receptors on the cell surface and stimulate the hydrolysis of phosphoinositides (PI). Any modulation by heavy metals in these may lead to altered calcium homeostasis. However, there are no definitive test hypotheses to evaluate the effects of mercury and lead on NT release, PI hydrolysis and calcium efflux. In view of this we propose to study the in vitro and in vivo influence of Hg++ and Pb++, on a) the binding of NTs (acetylcholine, norepinephrine and glutamate) to their specific receptors, b) phospholipase mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate, c) binding of Ins P3 and Ins P4 to their receptors and mobilization of Ca++, d) activation of PKC by diacylglycerol and its positive and/or negative feedback control of intracellular Ca++, e) Ca++-mediated catabolic enzymes such as lipases, proteases and endonucleases. All these experiments will be conducted in brain of male Sprague-Dawley rats. The proposed study establishes a relationship between the metal-induced changes in binding of NTs to their specific receptors, receptor-mediated PI hydrolysis and Ca++- homeostasis. Four (4) undergraduate students will participate in the proposed research. They will be trained in various biomedical research methodologies that are described in this project and also will be provided with research learning activities such as experience in library search, data analysis using computer, preparation of scientific manuscripts for publication and presentation at symposia or national scientific society meetings.
