To obtain a molecular insight into epilespy and develop optimal therapies for seizure disorders, it is important to understand the basic processes regulating neuronal excitability and how pathological processes interact with normal modulatory mechanisms that control neuronal activity. Although the precise molecular aspects of the regulation of excitability are not known, recent advances have been made in understanding the role that calcium, a major second messenger in neurons, plays in regulating neuronal excitability. Ca2+-calmodulin dependent protein kinase (CaM kinase II) has been implicated in regulating some of the effects of Ca2+ on cellular function and neuronal excitability. Studies in this research effort will test the Hypothesis that CaM kinase II is involved in mediating some of the regulatory effects of Ca2+ on specific membrane ion conductances. This project will coordinate biochemical, immunocytochemical and electrophysiological studies to determine whether endogenous CaM kinase II mediates the effects of Ca2+ on specific ion conductances in identified neurons of the nudibranch mollusc, Hermissenda crassicornis. Our Short-Term Goals are a) characterization of the effects of exogenous CaM kinase II on specific ion conductance in identified neurons, b) identification and characterization of endogenous CaM kinase II activity in these neurons, and c) immunocytochemical studies employing monoclonal antibodies to ascertain the cellular and subcellular distribution of CaM kinase II in these neurons. The Long Term Goas are a)investigation of whether neuronal excitation can modulate the activity of CaM kinase II, employing in vivo phosphorylation studies, b) characterization of the effects of monoclonal antibodies that have previously been demonstrated to regulate CaM kinase II activity on specific ion conductances, and c) correlation of the effects of pharmacological agents on endogenous CaM kinase II activity with their effects on specific ion conductances in neurons. The results may provide a molecular insight into an endogenous mechanism for modulating some of the effects of Ca2+ on neuronal excitability and may increase our understanding of the complex mechanisms that underlie the pathogenesis of seizure discharge and its regulation by anticonvulsant compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023350-09
Application #
3406723
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-07-01
Project End
1993-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Deshpande, Laxmikant S; Sombati, Sompong; Blair, Robert E et al. (2007) Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy. Neurosci Lett 411:11-6
Deshpande, Laxmikant S; Blair, Robert E; Nagarkatti, Nisha et al. (2007) Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus. Exp Neurol 204:705-13
Falenski, K W; Blair, R E; Sim-Selley, L J et al. (2007) Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 146:1232-44
Deshpande, Laxmikant S; Blair, Robert E; Ziobro, Julie M et al. (2007) Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol 558:52-9
Carter, Dawn S; Haider, S Naqeeb; Blair, Robert E et al. (2006) Altered calcium/calmodulin kinase II activity changes calcium homeostasis that underlies epileptiform activity in hippocampal neurons in culture. J Pharmacol Exp Ther 319:1021-31
Blair, Robert E; Deshpande, Laxmikant S; Sombati, Sompong et al. (2006) Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther 317:1072-8
DeLorenzo, Robert J; Sun, David A; Deshpande, Laxmikant S (2006) Erratum to ""Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy."" [Pharmacol. Ther. 105(3) (2005) 229-266] Pharmacol Ther 111:288-325
DeLorenzo, Robert J (2006) Epidemiology and clinical presentation of status epilepticus. Adv Neurol 97:199-215
Delorenzo, Robert J; Sun, David A; Deshpande, Laxmikant S (2005) Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintainance of epilepsy. Pharmacol Ther 105:229-66
Raza, Mohsin; Shaheen, Farzana; Choudhary, M I et al. (2004) Inhibition of sustained repetitive firing in cultured hippocampal neurons by an aqueous fraction isolated from Delphinium denudatum. J Ethnopharmacol 90:367-74

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