Since 1967, my research goal is focused on the issue of mechanism of transmitter released from sympathetic neuroeffector organs. In 1980, tissue culture technique was adopted with a hope that a pure population of sympathetic neurons (SN) would be available to study the molecular mechanism of transmitter release by determining the role of calcium ions (Ca) and other second messengers. Toward such a goal, several noradrenergic properties of cultured SN were established over the past 11 funding years. During the next support period we intend to probe further into the mechanism of release of norepinephrine (NE) by applying techniques not available in the past. Four major aspects of neurosecretion will be covered in the proposed research plan. 1. Physiological and pharmacological characteristics of 3H-NE release from two specialized regions of SN (I.E. cell body and nerve terminal or growth cone) will be evaluated. 2. Movements of Ca will be monitored in the cell body and the growth cones to know how these regions handle Ca and respond to agents that modulate 3H-NE release by affecting Ca. 3. Involvement of second messengers will be investigated on 3H-NE release and Ca movements to know how protein kinase C, inositol 1,4,5-triphosphate and cAMP cross-communicate to modulate release and neuronal Ca. 4. Trophic influence of heart cells on 3H_NE release and Ga-movements will be determined to know if heart cells modulate the release by affecting Ga movements in SN. Since the current proposal includes methods that are capable of giving more direct information, it is anticipated that upon completion of the present study a comprehensive picture will emerge concerning the role of Ca and other second messengers in the transmitter release process. Most important, these studies will provide new insights regarding the trophic influence of heart cells on their fields of innervation during growth and development. A number of preliminary results support the feasibility of the proposed research plan.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL018601-12A3
Application #
3335625
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1988-09-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
12
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wakade, A R; Przywara, D A; Bhave, S V et al. (1995) Cardiac cells control transmitter release and calcium homeostasis in sympathetic neurons cultured from embryonic chick. J Physiol 488 ( Pt 3):587-600
Lopez, M G; Shukla, R; Garcia, A G et al. (1992) A dihydropyridine-resistant component in the rat adrenal secretory response to splanchnic nerve stimulation. J Neurochem 58:2139-44
Malhotra, R K; Wakade, T D; Wakade, A R (1988) Comparison of secretion of catecholamines from the rat adrenal medulla during continuous exposure to nicotine, muscarine or excess K. Neuroscience 26:313-20
Malhotra, R K; Bhave, S V; Wakade, T D et al. (1988) Protein kinase C of sympathetic neuronal membrane is activated by phorbol ester--correlation between transmitter release, 45Ca2+ uptake, and the enzyme activity. J Neurochem 51:967-74
Wakade, A R; Wakade, T D; Malhotra, R K et al. (1988) Excess K+ and phorbol ester activate protein kinase C and support the survival of chick sympathetic neurons in culture. J Neurochem 51:975-83
Malhotra, R K; Wakade, T D; Wakade, A R (1988) Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis. J Biol Chem 263:2123-6
Malhotra, R K; Wakade, A R (1987) Vasoactive intestinal polypeptide stimulates the secretion of catecholamines from the rat adrenal gland. J Physiol 388:285-94
Malhotra, R K; Wakade, A R (1987) Non-cholinergic component of rat splanchnic nerves predominates at low neuronal activity and is eliminated by naloxone. J Physiol 383:639-52
Harish, O E; Kao, L S; Raffaniello, R et al. (1987) Calcium dependence of muscarinic receptor-mediated catecholamine secretion from the perfused rat adrenal medulla. J Neurochem 48:1730-5
Wakade, A R; Malhotra, R K; Wakade, T D (1986) Phorbol ester facilitates 45Ca accumulation and catecholamine secretion by nicotine and excess K+ but not by muscarine in rat adrenal medulla. Nature 321:698-700

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