Regulation of connexin hemichannels by monovalent cations.
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+.
Srinivas
Miduturu
M
State University of New York College of Optometry, New York, NY 10036, USA.
Calderon
D Paola
DP
Kronengold
Jack
J
Verselis
Vytas K
VK
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002414:Cations, Monovalent / Q000494:pharmacology*; D017630:Connexins / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D005136:Eye Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000494:pharmacology; D014982:Xenopus laevis; D000099264:Connexin 50
D002118:Calcium; D002414:Cations, Monovalent; D017630:Connexins; D005136:Eye Proteins; D007473:Ion Channels; D011188:Potassium; D012964:Sodium; D000099264:Connexin 50; C082917:GJA3 protein, human