Chapter 13: Behavior of Chemical and Slow Voltage-Sensitive Gates of Connexin Channels: The “Cork” Gating Hypothesis

Peracchia, Camillo; Wang, Xiao G.; Peracchia, Lillian L.

doi:10.1016/s0070-2161(08)61017-5

Cited by 15 publications

(38 citation statements)

References 55 publications

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“…Consistent with this view are also data from Cx32 mutants expressed heterotypically with Cx32wt in oocytes and tested in the presence and absence of CaM (26). The behavior of these mutants demonstrated the function of a slow gate sensitive to both CO 2 and transjunctional voltage (V j ) and suggested that the chemical gate and the slow gate are the same, and likely to be a sizable negatively charged particle (2,26). The slow kinetics of the chemical gate was demonstrated in single channel records (27).…”

supporting

confidence: 58%

“…As channels close, cells uncouple from each other electrically and metabolically. Uncoupling is mainly a protective mechanism, but evidence for channel gating sensitivity to nearly physiological [Ca 2ϩ ] i (2) suggests that it also participates in normal cellular functions. Although a number of uncoupling agents have been identified, little is known on channel gating mechanisms (3,4).…”

mentioning

confidence: 99%

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Calmodulin Directly Gates Gap Junction Channels

Peracchia

Sotkis

Wang

et al. 2000

Journal of Biological Chemistry

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103

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supporting

confidence: 58%

mentioning

confidence: 99%

Calmodulin Directly Gates Gap Junction Channels

Peracchia

Sotkis

Wang

et al. 2000

Journal of Biological Chemistry

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103

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“…The Ca 2 + –CaM induced gating response that closes the Cx43 gap junction is likely effected via a conformational change in the cytosolic loop of Cx43 [48]. It is also possible that, as proposed earlier by Peracchia and colleagues [91], Ca 2 + –CaM binds to the N‐ and C‐terminal domains of Cx32 to act as a “cork”, or it induces a conformational change in the cytosolic domain that occludes the cytosolic mouth of the gap junction channel, resulting in the restriction of the passage of current‐carry ions [60,92]. Unwin and Ennis proposed an alternative “iris” gating hypothesis that the extracellular Ca 2+ ‐induced closure of liver gap junctions is a result of a decrease in the tilt angle of six connexins within a connexon junction channel [93].…”

Section: Molecular Basis Of Cam Regulation Of Connexinsmentioning

confidence: 69%

Gap junction regulation by calmodulin

et al. 2014

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Intracellular Ca2+ activated calmodulin (CaM) inhibits gap junction channels in the low nM to high μM range of [Ca2+]i. This regulation plays an essential role in numerous cellular processes that include hearing, lens transparency, and synchronized contractions of the heart. Previous studies have indicated that gap junction mediated cell-to-cell communication was inhibited by CaM antagonists. More recent evidence indicates a direct role of CaM in regulating several members of the connexin family. Since the intracellular loop and carboxyl termini of connexins are largely “invisible” in electron microscopy and X-ray crystallographic structures due to disorder in these domains, peptide models encompassing the putative CaM binding sites of several intracellular domains of connexins have been used to identify the Ca2+-dependent CaM binding sites of these proteins. This approach has been used to determine the CaM binding affinities of peptides derived from a number of different connexin-subfamilies.

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“…For instance, liver gap junctions, composed predominantly of Cx32, may possess connexin CaM binding amino and carboxyl terminal domains instead of the Cx43 CL site (14,54). Holo CaM may act directly as a "cork" or induce a conformational change in the CL domain that occludes the cytoplasmic vestibule (mouth) of the gap junction channel, thereby restricting the passage of current-carrying ions (14,45). There are several possible Ca 2ϩ / CaM gating mechanisms for connexin gap junctions that could be considered (Fig.…”

Section: Discussionmentioning

confidence: 99%

Gating of connexin 43 gap junctions by a cytoplasmic loop calmodulin binding domain

Kopp

Chen

et al. 2012

American Journal of Physiology-Cell Physiology

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Calmodulin (CaM) binding sites were recently identified on the cytoplasmic loop (CL) of at least three α-subfamily connexins (Cx43, Cx44, Cx50), while Cx40 does not have this putative CaM binding domain. The purpose of this study was to examine the functional relevance of the putative Cx43 CaM binding site on the Ca(2+)-dependent regulation of gap junction proteins formed by Cx43 and Cx40. Dual whole cell patch-clamp experiments were performed on stable murine Neuro-2a cells expressing Cx43 or Cx40. Addition of ionomycin to increase external Ca(2+) influx reduced Cx43 gap junction conductance (G(j)) by 95%, while increasing cytosolic Ca(2+) concentration threefold. By contrast, Cx40 G(j) declined by <20%. The Ca(2+)-induced decline in Cx43 G(j) was prevented by pretreatment with calmidazolium or reversed by the addition of 10 mM EGTA to Ca(2+)-free extracellular solution, if Ca(2+) chelation was commenced before complete uncoupling, after which g(j) was only 60% recoverable. The Cx43 CL(136-158) mimetic peptide, but not the scrambled control peptide, or Ca(2+)/CaM-dependent kinase II 290-309 inhibitory peptide also prevented the Ca(2+)/CaM-dependent decline of Cx43 G(j). Cx43 gap junction channel open probability decreased to zero without reductions in the current amplitudes during external Ca(2+)/ionomycin perfusion. We conclude that Cx43 gap junctions are gated closed by a Ca(2+)/CaM-dependent mechanism involving the carboxyl-terminal quarter of the connexin CL domain. This study provides the first evidence of intrinsic differences in the Ca(2+) regulatory properties of Cx43 and Cx40.

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Chapter 13: Behavior of Chemical and Slow Voltage-Sensitive Gates of Connexin Channels: The “Cork” Gating Hypothesis

Cited by 15 publications

References 55 publications

Calmodulin Directly Gates Gap Junction Channels

Calmodulin Directly Gates Gap Junction Channels

Gap junction regulation by calmodulin

Gating of connexin 43 gap junctions by a cytoplasmic loop calmodulin binding domain

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