Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons

Abstract

Recent evidence indicating formation of functional homomeric/heterotypic gap junction channels by connexin40 (Cx40) and connexin43 (Cx43) raises the question of whether data previously interpreted as support for heteromeric channel formation by these connexins might not instead reflect the activity of homomeric/heterotypic channels. To address this question and to further characterize the behavior of these channels, we used dual whole cell voltage-clamp techniques to examine the junctions formed between cells that express only Cx40 (Rin40) or Cx43 (Rin43) and compared the results with those obtained when either of these cell types was paired with cells that naturally express both connexins (A7r5 cells). Rin40/Rin43 cell pairs formed functional gap junctions that displayed a strongly asymmetric voltage-dependent gating response. Single-channel event amplitudes ranged between 34 and 150 pS, with 90- to 130-pS events predominating. A7r5/Rin43 and A7r5/Rin40 cell pairs had voltage-dependent gating responses that varied greatly, with most pairs demonstrating strong asymmetry. These cell pairs exhibited a variety of single-channel events that were not consistent with homomeric/homotypic Cx40 or Cx43 channels or homomeric/heterotypic Cx40/Cx43 channels. These data indicate that Cx40 and Cx43 form homomeric/heterotypic as well as heteromeric/heterotypic channels that display unique gating and conductance properties.

Neonatal Rat Cardiomyocytes Show Characteristics of Nonhomotypic Gap Junction Channels

“…The inactivation was more prominent for negative V j as for positive V j , resulting in an inactivation curve that has almost exactly the same shape as the one summarizing our findings for neonatal rat cardiomyocytes. Cottrell and Burt (2001) found the same strong asymmetry for Cx40-Cx43 homomericheterotypic gap junction channels in coculture of Cx40-and Cx43-transfected RIN cells.…”

“…Heterotypic gap junction channels have been studied by many authors (Valiunas et al 2000;Cottrell, Burt 2001;Cottrell et al 2002;Elenes et al 2001;Desplantez et al 2004). All authors describe a nonsymmetrical gating behavior of the different investigated heterotypic channels (Cx40-Cx43, Cx40-Cx45, and Cx43-Cx45).…”

Functional consequences of co-expressing connexin40 or connexin45 with connexin43 on intercellular electrical coupling

“…It was shown that contrary to this study, deletion of one connexin in myocardium of transgenic mice was not accompanied by a compensatory change in expression of another connexin [18]. of electrical coupling in response to alterations to Cx40:Cx43 co-expression ratios; even when dye transfer is substantially altered [5].…”

Sharing signals: connecting lung epithelial cells with gap junction channels

“…However, this has turned out not to be the case, particularly for heterotypic interactions, since these interactions are sensitive to subtle changes in the sequence of the second extracellular loop domain often missed by normal amino acid homology comparisons. For instance, Cx40 and Cx43 have the capacity to form heteromeric gap junction channels (38,55,274,275), but Cx43 hemichannels cannot pair with Cx40 hemichannels to form functional gap junctions (34,80,119,296). Cx46 represents another exception to the normal restrictions in connexin compatibility, since it can apparently form heterotypic channels with almost every connexin (293, 296), whether or not it can form heteromeric channels with them (59).…”

“…Cx32 is fully permeable to cAMP and cGMP; however, on the basis of assays of reconstituted channels, Cx32/Cx26 heteromers are preferentially permeable to cGMP compared with cAMP (21), indicating that the stoichiometry of Cx26 to Cx32 enables cells to fine tune metabolic coupling through these channels. There are other examples of heteromeric gap junction channels that have unique permeability characteristics, including Cx37/ Cx43 (30, 164), Cx40/Cx43 (38,55,274,275), and Cx43/Cx45 (148,191).…”