PKC MODULATION OF GS8 AND CALCIUM CHANNEL INTERACTIONS

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DESCRIPTION: (Applicant's Abstract) My predoctoral and post- doctoral background consists of behavioral, neurochemical, biochemical and molecular biology studies. During my postdoctoral years under the supervision of Dr. Boris Tabakoff, Department of Pharmacology, UCHSC, I developed a special interest and expertise in G protein-mediated signal transduction, especially in the family of adenylyl. cyclases. Now my goal is to expand my expertise in this area and to acquire skills needed to study how G proteins regulate another class of effectors, the voltagegated calcium channels. In the proposed training I will learn electrophysiology, especially whole cell patch clamp recordings. This technique will allow me to measure events of G protein regulation of the channels in the time scale of milliseconds-seconds, as opposed to the time scale of minutes in the adenylyl cyclase enzyme assays. The proposed training will be take place in Dr. William Sather's (Mentor) laboratory at the Deparunent of Pharmacology, UCHSC. Dr. Sather's laboratory uses routinely electrophysiological techniques, such as whole cell and single channel patch clamp and two-electrode voltage clamp techniques. The Co-Mentor, Dr. Thomas Dunwiddie is another expert electrophysiologist. These laboratories and the Department provide excellent facilities and intellectual milieu. The research project will focus on protein kinase C (PKC) and G protein modulation of N- and P/Q-type calcium channels. Gi/Go- coupled receptors have been demonstrated to inhibit, in a membrane- delimited manner, N- and P/Q-type channels that are involved in neurotransmitter release in the CNS. Recent studies have shown that GBy subunits which are released upon Gi/Go-coupled receptor stimulation are directly interacting with the chafifiel al subunits inhibiting the channel function. On the other hand, there is evidence that activation of PKC antagonizes the membrane-delimited inhibition of calcium channels by GBy. The aim of the proposed studies is to investigate in detail the role of different PKC isozymes and the mechanisms how these isozyntes modulate the interactions of Gpy with N (alB)- and PIQ (aW-type channels. This training will allow me in the future to write proposals and receive funding for studies on G protein regulation of different effector classes as a fully independent investigator, which will advance my career in the academic environment. Calcium channels play a key role in neurons and have been implicated as targets of diverse neurological diseases, such as familial herniplegic migraine, episodic ataxia I type 2 and spinocerebellar ataxia 6.