Abstract
In the past four decades numerous findings have indicated that gap junction channel gating is mediated by intracellular calcium concentrations ([Ca2+i]) in the high nanomolar range via calmodulin (CaM). We have proposed a CaM-based gating model based on evidence for a direct CaM role in gating. This model is based on the following: CaM inhibitors and the inhibition of CaM expression to prevent chemical gating. A CaM mutant with higher Ca2+ sensitivity greatly increases gating sensitivity. CaM co-localizes with connexins. Connexins have high-affinity CaM-binding sites. Connexin mutants paired to wild type connexins have a higher gating sensitivity, which is eliminated by the inhibition of CaM expression. Repeated trans-junctional voltage (Vj) pulses progressively close channels by the chemical/slow gate (CaM’s N-lobe). At the single channel level, the gate closes and opens slowly with on-off fluctuations. Internally perfused crayfish axons lose gating competency but recover it by the addition of Ca-CaM to the internal perfusion solution. X-ray diffraction data demonstrate that isolated gap junctions are gated at the cytoplasmic end by a particle of the size of a CaM lobe. We have proposed two types of CaM-driven gating: “Ca-CaM-Cork” and “CaM-Cork”. In the first, the gating involves Ca2+-induced CaM activation. In the second, the gating occurs without a [Ca2+]i rise.
Highlights
Direct ionic communication between electrically excitable cells was discovered in the early 20th century [1,2], but for many decades this form of cell–cell communication was thought to be a property of excitable cells only
As gap junction proteins do not have highly sensitive intracellular Ca2+ -binding sites, the data described in the previous chapter strongly suggest that Ca2+ i affects gating via an intermediate component
Since the early eighties we have proposed calmodulin (CaM) as the intermediate of the Ca2+ gating effect; rev. in: [50,51,52]
Summary
Direct ionic communication between electrically excitable cells was discovered in the early 20th century [1,2], but for many decades this form of cell–cell communication was thought to be a property of excitable cells only. Some hints of the existence of cell–cell uncoupling mechanisms originated almost a century earlier. In 1877 Engelmann reported that damaged cardiac cells became independent from their neighboring cells as they died [10]. This phenomenon, called “healing over”, is known as “cell-to-cell uncoupling”, a property of all coupled cells, mediated by the chemical gating mechanism of gap junction channels; rev. This phenomenon, called “healing over”, is known as “cell-to-cell uncoupling”, a property of all coupled cells, mediated by the chemical gating mechanism of gap junction channels; rev. in [11,12,13,14,15]
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