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A Novel Calcium-Activated Apamin-Insensitive Potassium Current in Pituitary Gonadotrophs

Laboratory of Cell Biology and Biochemistry, National Institute of Diabetes and Digestive and Kidney Disorders, and Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Stanko Stojilkovic, NICHD/ERRB/UCS, Building 49, Room 6A-36, 49 Convent Drive, MSC 4510, Bethesda, Maryland 20892-4510. E-mail: stankos{at}helix.nih.gov

In cultured rat pituitary gonadotrophs, GnRH-induced oscillations in cytosolic calcium concentration ([Ca²⁺]_i) are associated with periodic membrane hyperpolarization. The hyperpolarizing waves are secondary to the activation of apamin-sensitive Ca²⁺-activated K⁺ channels that account for a single class of ¹²⁵I-apamin binding sites present in these cells. In a substantial fraction of gonadotrophs, however, we observed a Ca²⁺-controlled oscillatory current that was resistant to apamin, even at concentrations five orders of magnitude higher than the dissociation constant (K_d) observed in the binding experiments. With the K⁺ in the pipette, the apamin-resistant current showed a reversal potential of -42 mV, nearly 40 mV more positive than that of the apamin-sensitive current. With Cs⁺ in place of K⁺ in the pipette solution, both the size of the apamin-insensitive current and its reversal potential remained unchanged. Ion substitution studies further revealed that the reversal potential was independent of Cl^-. In contrast, an 11 mV hyperpolarizing shift in the reversal potential occurred when extracellular Na⁺ was reduced to 80 mM. In cells expressing apamin-resistant conductances, addition of apamin evoked a marked increase in the duration of the action potentials and reduction in the frequency of spontaneous spiking. In the presence of GnRH, gonadotrophs exhibit the typical burst pattern of electrical activity. Further exposure of the cells to apamin depolarized the membrane from a silent phase bursting level of about -80 mV to a new level of about -40 mV. These observations indicate that, in addition to apamin-sensitive current, a subpopulation of pituitary gonadotrophs also expresses a cationic component of the Ca²⁺-activated membrane conductance that has the potential to remodulate spontaneous and agonist-induced electrical activity.