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Circulation Research. 1995;77:1156-1165

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(Circulation Research. 1995;77:1156-1165.)
© 1995 American Heart Association, Inc.


Articles

Selectivity of Connexin-Specific Gap Junctions Does Not Correlate With Channel Conductance

Richard D. Veenstra, Hong-Zang Wang, Dolores A. Beblo, Mark G. Chilton, Andrew L. Harris, Eric C. Beyer, Peter R. Brink

From the Department of Pharmacology (R.D.V., H.-Z.W., D.A.B., M.G.C.), State University of New York Health Science Center at Syracuse; the Department of Biophysics (A.L.H.), Johns Hopkins University, Baltimore, Md; the Department of Pediatrics and Cell Biology and Department of Physiology (E.C.B.), Washington University School of Medicine, St Louis, Mo; and the Department of Physiology and Biophysics (P.R.B.), State University of New York Health Science Center at Stony Brook.

Correspondence to Dr Richard D. Veenstra, Department of Pharmacology, SUNY Health Science Center at Syracuse, Syracuse, NY 13210. E-mail veenstrr@vax.cs.hscsyr.edu.

Abstract Connexins form a variety of gap junction channels that vary in their developmental and tissue-specific levels of expression, modulation of gating by transjunctional voltage and posttranslational modification, and unitary channel conductance ({gamma}j). Despite a 10-fold variation in {gamma}j, whether connexin-specific channels possess distinct ionic and molecular permeabilities is presently unknown. A major assumption of the conventional model for a gap junction channel pore is that {gamma}j is determined primarily by pore diameter. Hence, molecular size permeability limits should increase and ionic selectivity should decrease with increasing channel {gamma}j (and pore diameter). Equimolar ion substitution of 120 mmol/L KCl for potassium glutamate was used to determine the unitary conductance ratios for rat connexin40 and connexin43, chicken connexin43 and connexin45, and human connexin37 channels functionally expressed in communication-deficient mouse neuroblastoma (N2A) cells. Comparison of experimental and predicted conductance ratios based on the aqueous mobilities of all ions according to the Goldman-Hodgkin-Katz current equation was used to determine relative anion-to-cation permeability ratios. Direct correlation of junctional conductance with dye transfer of two fluorescein-derivatives (2 mmol/L 6-carboxyfluorescein or 2',7'-dichlorofluorescein) was also performed. Both approaches revealed a range of selectivities and permeabilities for all five different connexins that was independent of channel conductance. These results are not consistent with the conventional simple aqueous pore model of a gap junction channel and suggest a new model for connexin channel conductance and permselectivity based on electrostatic interactions. Divergent conductance and permeability properties are features of other classes of ion channels (eg, Na+ and K+ channels), implying similar mechanisms for selectivity.


Key Words: gap junction • channel • selectivity • 6-carboxyfluorescein • 2',7'-dichlorofluorescein




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