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Received December 9, 2003
Revised February 9, 2004
Accepted after revision April 23, 2004
1 SUNY
2 University of Chicago
* To whom correspondence should be addressed. E-mail: veenstrr{at}upstate.edu.
Connexin40 (Cx40) contains a specific binding site for
spermine (affinity 
100 µM) whereas connexin43
(Cx43) is unaffected by identical concentrations of
intracellular spermine. Replacement of two unique
glutamate residues, E9 and E13, from the cytoplasmic amino
terminal domain of Cx40 with the corresponding lysine
residues from Cx43 eliminated the block by 2 mM spermine,
reduced the transjunctional voltage (Vj) gating
sensitivity, and reduced the unitary conductance of this
Cx40E9,13K gap junction channel protein. The single point
mutations, Cx40E9K and Cx40E13K, predominantly affected
the residual conductance state (Gmin) and
Vj gating properties, respectively.
Heterotypic pairing of Cx40E9,13K with wild-type Cx40 in
murine neuro2A (N2A) cells produced a strongly rectifying
gap junction reminiscent of the inward rectification
properties of the Kir (e.g. Kir2.x) family of potassium
channels. The reciprocal Cx43K9,13E mutant protein
exhibited reduced Vj sensitivity, but
displayed much less rectification in heterotypic pairings
with wtCx43, negligible changes in the unitary channel
conductance, and remained insensitive to spermine block.
These data indicate that the connexin40 amino terminus may
form a critical cytoplasmic pore-forming domain that
serves as the receptor for Vj-dependent closure
and block by intracellular polyamines. Functional
reciprocity between Cx40 and Cx43 gap junctions involves
other amino acid residues in addition to the E or K 9 and
13 loci located on the amino terminal domain of these two
connexins.
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