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J. Biol. Chem., Vol. 278, Issue 50, 49685-49690, December 12, 2003

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High Extracellular Ca²⁺ Hyperpolarizes Human Parathyroid Cells via Ca²⁺-activated K⁺ Channels^*

Stiina Välimäki, Anders Höög¶, Catharina Larsson, Lars-Ove Farnebo||, and Robert Bränström

From the Departments of Molecular Medicine, Surgical Sciences, and ^¶Oncology and Pathology, Karolinska Hospital, Karolinska Institutet, SE-171 76 Stockholm, Sweden

Membrane potential has a major influence on stimulus-secretion coupling in various excitable cells. The role of membrane potential in the regulation of parathyroid hormone secretion is not known. High K⁺-induced depolarization increases secretion from parathyroid cells. The paradox is that increased extracellular Ca²⁺, which inhibits secretion, has also been postulated to have a depolarizing effect. In this study, human parathyroid cells from parathyroid adenomas were used in patch clamp studies of K⁺ channels and membrane potential. Detailed characterization revealed two K⁺ channels that were strictly dependent of intracellular Ca²⁺ concentration. At high extracellular Ca²⁺, a large K⁺ current was seen, and the cells were hyperpolarized (–50.4 ± 13.4 mV), whereas lowering of extracellular Ca²⁺ resulted in a dramatic decrease in K⁺ current and depolarization of the cells (–0.1 ± 8.8 mV, p < 0.001). Changes in extracellular Ca²⁺ did not alter K⁺ currents when intracellular Ca²⁺ was clamped, indicating that K⁺ channels are activated by intracellular Ca²⁺. The results were concordant in cell-attached, perforated patch, whole-cell and excised membrane patch configurations. These results suggest that [Ca²⁺]_o regulates membrane potential of human parathyroid cells via Ca²⁺-activated K⁺ channels and that the membrane potential may be of greater importance for the stimulus-secretion coupling than recognized previously.

Received for publication, September 24, 2003

^* This study was supported by the Biomed BMH4-97-2225, the Swedish Medical Research Council, the Swedish Cancer Foundation, the Torsten and Ragnar Söderberg Foundations, the Nilsson-Ehle Foundation, the Robert Lundberg Foundation and, the Novo Nordisk Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Surgical Sciences, Karolinska Institutet, Karolinska Hospital P9:03, SE-171 76 Stockholm, Sweden. Tel.: 46-8-517-73727; Fax: 46-8-33-15-87; E-mail: lars-ove.farnebo{at}kirurgi.ki.se.

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