© 1995 American Heart Association, Inc.
Articles |
Selectivity of Connexin-Specific Gap Junctions Does Not Correlate With Channel Conductance
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
(
j). Despite a 10-fold variation in
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 j is determined primarily by pore diameter.
Hence, molecular size permeability limits should increase and ionic
selectivity should decrease with increasing channel 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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