LKS AND LKUR IN GRANULOSA CELLS

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The long-term goals of the research are to increase knowledge about ion channels present in ovarian granulosa cells (GC), and suggest potential roles for ion channels in GC function. The proposed project will focus specifically on the regulatory properties and functional significance of: a slowly activating, non-inactivating delayed rectifier K+ current (IKs), and an utra-rapidly activating delayed rectifier K+ curren (IKur). The major hypotheses to be tested are 1) IKs and IKur are modulated by signal transduction systems implicated in granulosa cell growth and differentiation; 2) IKs, IKur, or both potassium conductances are required for normal granulosa cell maturation. Electrophysiological and cell culture techniques will be used to address these hypotheses experimentally. Biochemical techniques will be used to define the channel proteins that contribute to IKur. Specifically, experiments were designed to: 1) Compare the properties of granulosa cell IKs to those of the cardiac slow delayed rectifier K+ current, and those of the slow K+ currents associated with co-expression of min-K and KvLQT1, the channel proteins that associate to form functional Ks channels; 2) Compare the properties of granulosa cell IKur to those of delayed rectifier K+ currents in other cell types, and delayed rectifier K+ currents associated with expression of the Kv (Shaker subfamily) channel proteins that contribute to IKur; 3) Determine whether or not the inhibitory effects of various K+ channel antagonists on granulosa cell maturation are related to blockade of IKs or IKur. It will be critical not only to define the physiological role(s) of IKs and IKur in GC maturation, but also to compare the pharmacological profiles of the GC currents to those of delayed rectifier currents in other cells. K+ channels have been identified as therapeutic targets in heart, smooth muscle, lymphocytes, and brain (Carmeleit, 1991). GC IKs and IKur may represent either novel targets for assisted reproduction, or potential sites of toxicity for drugs designed to treat arrhythmias, asthma, incontinence, immunosuppression or epilepsy.