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¹ State University of New York College of Optometry, New York, NY 10036
² Albert Einstein College of Medicine, Bronx, NY 10561

Correspondence to Vytas K. Verselis: verselis{at}aecom.yu.edu

Opening of connexin hemichannels in the plasma membrane is highly regulated. Generally, depolarization and reduced extracellular Ca²⁺ promote hemichannel opening. Here we show that hemichannels formed of Cx50, a principal lens connexin, exhibit a novel form of regulation characterized by extraordinary sensitivity to extracellular monovalent cations. Replacement of extracellular Na⁺ with K⁺, while maintaining extracellular Ca²⁺ constant, resulted in >10-fold potentiation of Cx50 hemichannel currents, which reversed upon returning to Na⁺. External Cs⁺, Rb⁺, NH₄⁺, but not Li⁺, choline, or TEA, exhibited a similar effect. The magnitude of potentiation of Cx50 hemichannel currents depended on the concentration of extracellular Ca²⁺, progressively decreasing as external Ca²⁺ was reduced. The primary effect of K⁺ appears to be a reduction in the ability of Ca²⁺, as well as other divalent cations, to close Cx50 hemichannels. Cx46 hemichannels exhibited a modest increase upon substituting Na⁺ with K⁺. Analyses of reciprocal chimeric hemichannels that swap NH₂- and COOH-terminal halves of Cx46 and Cx50 demonstrate that the difference in regulation by monovalent ions in these connexins resides in the NH₂-terminal half. Connexin hemichannels have been implicated in physiological roles, e.g., release of ATP and NAD⁺ and in pathological roles, e.g., cell death through loss or entry of ions and signaling molecules. Our results demonstrate a new, robust means of regulating hemichannels through a combination of extracellular monovalent and divalent cations, principally Na⁺, K⁺, and Ca²⁺.

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This article has been cited by other articles:

				F. Liu, F. T. Arce, S. Ramachandran, and R. Lal Nanomechanics of Hemichannel Conformations: CONNEXIN FLEXIBILITY UNDERLYING CHANNEL OPENING AND CLOSING J. Biol. Chem., August 11, 2006; 281(32): 23207 - 23217. [Abstract] [Full Text] [PDF]

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