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  • br Methods br Results br Discussion In this


    Discussion In Nilvadipine this study, we investigated temperature effects on Vj-gating properties of two cardiac GJs. In the case of Cx45 GJs, increased temperature from 22 °C to 28 °C (or 32 °C) led to an accelerated Vj-dependent deactivation with little change in the extent of Vj-gating (a minimum change in Boltzmann parameter, Gmin) at the tested Vj range. The rate of recovery from deactivation of Cx45 GJs was also accelerated at higher temperatures. The dynamic uncoupling with our designed protocol was evident in Cx45 GJs when sufficient junctional delay and/or repeating frequency provided. However, in the same tested temperatures Cx40 GJs showed no change in the rate of recovery from deactivation, no change in the Boltzmann fitting parameters for the Vj-gating, and no dynamic uncoupling in any of our tested junctional delays and/or repeating frequencies. The only temperature-dependent effect of Cx40 GJs was an accelerated Vj-dependent deactivation kinetics. The time constants of the recovery time course from deactivation of Cx40 GJs were much shorter (~70–100 fold shorter) than those of Cx45 GJs. The unique dynamic uncoupling of Cx45 GJs may play a role in a slower AV node conduction and preventing high rate of ventricular beating from fibrillating atria in atrial fibrillation patients.
    Funding This work was supported by Canadian Institutes of Health Research (153415 to D.B.). A.S-M. was supported by a grant from FAPEMIG from Brazil.
    Introduction Presently, there are at least 21 known human connexin genes [1]. For each connexin protein there is a documented homotypic gap junction channel form composed of 12 identical connexins where 6 identical connexins form a hemichannel in each cell of a cell pair. Heterotypic gap junction Nilvadipine are formed by two non-identical hemichannels. Heteromeric channels are formed by hemichannels that are composed of more than one connexin type. For any two mutually compatible connexins there are, in theory, 196 gap junction channel types possible [2], either as a heteromeric or heterotypic form. In principle, it is therefore possible to have hundreds if not thousands of different channel types. The in vivo state of affairs for connexin expression and thus functionality is clearly complicated by the potential for multiple connexin expression [1], [3], [4], which is hampered by yet another factor, the rapid turnover rates of the connexin protein subunits [5]. To understand the biophysical properties of gap junction channels composed of connexins, researchers have used connexin deficient cell types transfected with DNA for a single connexin. This allows analysis of the physical properties that govern homotypic gap junction channel function. A number of groups have studied properties such as fluorescent probe and second messenger permeability as well as unitary conductance to better understand the molecular nature of gap junction permeability and selectivity [6], [7]. In this review we will use data from a number of published works to elucidate some of the experimentally deduced properties of gap junction pore selectivity/permeability and discuss the possible underlying molecular mechanisms.
    A broad spectrum of permeant ions and solutes Initial observations of single gap junction channels revealed unitary conductances of over one hundred picosiemens [21], [22]. Subsequent identification of the connexin family [23] resulted in numerous studies where measurements of homotypic channels revealed that connexins were permeable to more than one monovalent ion and also allowed the transit of fluorescent probes [6], [14], [24], [25], [26], polypeptides [27], and oligonucleotides [19]. Initially, the observation that varied ions and solutes are able to transit from one cell to another via gap junctions resulted in the belief that the channels were non-selective, with the solute size and charge as the only rate limiting steps [6]. However, a number of studies, including that of Elfgang et al. [28], showed that specific homotypic and heterotypic gap junction channels displayed different apparent permeabilities to a number of fluorescent probes, leading to the suggestion that not all connexins function the same, especially for solutes in the size range of second messengers [26]. Data like that shown by Elfgang et al. and others [26], [29], [30] have led many to speculate: is there any evidence for cation or anion selectivity in gap junction channels?