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Biophysical Characteristics of Gap Junctions in Vascular Wall Cells: Implications for Vascular Biology and Disease

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Biophysical Characteristics of Gap Junctions in Vascular Wall Cells: Implications for Vascular Biology and Disease Brazilian Journal of Medical and Biological Research (2000) 33: 415-422 Gap junctions in vascular wall cells 415 ISSN 0100-879X Biophysical characteristics of gap junctions in vascular wall cells: implications for vascular biology and disease P.R. Brink1, Departments of 1Physiology and Biophysics, Institute for Molecular Cardiology, and J. Ricotta2 and 2Surgery, SUNY at Stony Brook, Stony Brook, NY, USA G.J. Christ3,4 Departments of 3Urology, and 4Physiology and Biophysics, Institute for Smooth Muscle Biology, Albert Einstein College of Medicine, Bronx, NY, USA Abstract Correspondence The role gap junction channels play in the normal and abnormal Key words P.R. Brink functioning of the vascular wall is the subject of much research. The · Vascular smooth muscle Department of Physiology and biophysical properties of gap junctions are an essential component in · Gap junctions Biophysics understanding how gap junctions function to allow coordinated relax- SUNY at Stony Brook ation and contraction of vascular smooth muscle. This study reviews Stony Brook, NY 11794 USA the properties thus far elucidated and relates those properties to tissue function. We ask how biophysical and structural properties such as Presented at the Meeting gating, permselectivity, subconductive states and channel type (het- “Gap Junctions in the Nervous and eromeric vs homotypic vs heterotypic) might affect vascular smooth Cardiovascular Systems: Clinical muscle tone. Implications”, Rio de Janeiro, RJ, Brazil, June 6-11, 1998. Research supported by NIH grant GM55263. Introduction subject of modeling strategies which rely on gap junction-mediated communication to In vascular smooth muscle the role that produce tissue responses to stimuli which Received August 13, 1999 gap junctions play is integral among a num- mimic reality (8,9). For this reason, the bio- Accepted November 23, 1999 ber of other processes and parameters influ- physical characteristics of gap junction chan- encing tissue function (1-4). The ultimate nels in vascular smooth muscle and associ- tissue function, however, is coordinated re- ated vascular wall cells, such as endothelial laxation and contraction of the many cells cells, should be elucidated. In particular, for within the wall of any particular vessel. Ulti- example, are there gap junctional properties mately, the major factors which influence which lend themselves to dynamic regula- such coordinated tissue behavior are neu- tion? How many gap junction channels are ronal innervation density, cell to cell com- needed to allow cells to act syncytially? What munication and cellular excitability (1,5-7). types of gap junction channels are present in As vascular smooth muscle cells do not tend the vascular wall? Is it possible that hybrid to generate action potentials, innervation channel types exist in vascular smooth density and gap junction-mediated commu- muscle, and if so, would their presence affect nication become paramount as potential regu- tissue function? These issues are considered latory sites. The former parameter is the herein. Braz J Med Biol Res 33(4) 2000 416 P.R. Brink et al. Results and Discussion tion channels and subsequently compare their behavior to Cx37, Cx40 and Cx45 whenever Generic gap junction channel types in possible. In this regard, the instantaneous vascular tissues junctional current for Cx43 is linear over a large voltage range. Transjunctional voltage The subunit protein of any gap junction steps of sufficient amplitude and duration channel is the connexin and in vascular cause junctional currents to decline with smooth muscle connexin43 (Cx43) is the time, resulting in a steady-state conductance most abundant, followed by connexin40 which is a fraction of the instantaneous con- (Cx40), connexin45 (Cx45) and possibly ductance. The time course of the voltage- connexin37 (Cx37) (1,10-12). Endothelial dependent behavior is of the order of hun- cells are also able to co-express Cx43, Cx40 dreds of milliseconds to seconds (13). Cx43 and Cx37, the latter being the most abundant shows relatively symmetric voltage depend- in situ (see 1 for review). ence but has different voltage sensitivity The putative presence of multiple con- relative to Cx37. That is, the point on the Vj nexin subtypes in a given vascular smooth axis where junctional conductance is 50% of muscle cell has potentially important physi- the maximum (i.e., Vo) is approximately 25- ological implications. For example, there are 30 mV for Cx37 and 70-85 mV for Cx43 three types of gap junction channels possible (12,14,15). Cx40 has a Vo in the 40 mV when more than one connexin is being ex- range, while the Vo for Cx45 has been pressed in the same cell. They are as follows: reported to be 20 mV (16). Such observa- 1) a homotypic gap junction channel com- tions emphasize that, with the possible ex- posed of 12 identical connexin subunits, 2) a ception of Cx45, the voltage sensitivity of heterotypic gap junction channel where all connexins in vascular wall cells is not likely the connexins of one cell are identical but to effect dynamic changes in intercellular different from the connexins of the adjacent coupling. cell, and 3) the heteromeric gap junction Analysis of the junctional gating over channel where the connexins in any one cell many seconds to minutes has revealed, in the are not identical within a hemichannel. In case of Cx43, another wrinkle to gating, and the case of vascular smooth muscle cells the that is mode shifting. The process has been dominant connexin is Cx43. Therefore, we described in detail (13). Two important fea- will focus our discussion on properties of tures must be considered here. First, the time homotypic gap junction channels composed course to reach steady state was of the order of Cx43, Cx40, Cx45 and Cx37. Further we of 60 s or longer, and second, the mechanism will compare homotypic Cx43 and Cx37 to could not be explained as a simple reduction the in vitro documentation of Cx43-Cx37 of mean open time or increase in mean closed heterotypics and heteromerics. The relevant time for an identical population of channels. properties to be described are gating and Rather, a large portion of the channel popu- permselectivity. lation (90%) underwent a shift to prolonged silence (prolonged closure) leaving only a Homotypic gap junction membrane voltage small population of functional channels. The dependence process was reversible. Again, this is a volt- age-dependent process and the magnitude In general, all mammalian homotypic gap and duration of the voltage steps (30-50 mV, junction channels display symmetric voltage with durations of many seconds) seem to be dependence. Because of its ubiquity we will outside the physiologically useful range. first characterize Cx43 homotypic gap junc- However, it should be pointed out that if this Braz J Med Biol Res 33(4) 2000 Gap junctions in vascular wall cells 417 process is modified or driven in the presence that the permselective properties of the sub- of physiologically important ligands/intra- conductive states are very different from the cellular messengers, such as cAMP or IP3, it main state conductance has given rise to could well be a regulatory point with great much speculation. For example, if the sub- dynamic range. This latter postulate has yet conductive state is the dominant one in terms to be experimentally tested, let alone shown of dwell time, then it would necessarily fol- to be functional under physiological condi- low that the permeation rates of solutes seek- tions. Mode shifting has not been character- ing transit from cell to cell would be quite ized for Cx37 but has been demonstrated in dependent on the nature of the subconducting A7r5 cells which co-express Cx40 and Cx43 state(s). However, before even addressing (He DS, personal communication). Thus, the permselective properties, the first ques- voltage-dependent gating, a common prop- tion answered must be how much of the open erty of all the vertebrate connexins thus far time is dominated by subconductive states. studied, seems to be an unlikely tool for cells If the dwell time in any given subconductance to utilize in order to affect dynamic alter- state is significant (10-20% or greater?), then ations in cell to cell coupling mediated by the permeation characteristics of the distinct gap junctions. Whether ligand gating, linked subconducting states become of interest. For with processes such as mode shifting, might Cx43, Christ and Brink (24) have deter- be able to provide dynamic behaviors that mined that the occupancy time of the sub- are physiologically relevant to the vascular conductive state(s), for a transjunctional volt- wall cell has yet to be determined. age of 40 mV, is less than 2% for a channel whose open probability is on the order of 70- Homotypic gap junction channel 90%. In this case, even if the permselectivity conductance of the subconductive state is dramatically different from the main state it would seem The unitary conductance for Cx43 is 90- hardly relevant to macroscopic tissue behav- 120 pS (13,17- 20). Table 1 lists the unitary ior with such a low occupancy time. Con- conductances for all four connexin types versely, if gap junction channels are driven found in the vascular system. The different into subconductive states by interaction with unitary conductance values imply that dif- ligands, or alterations in second messenger ferent permselectivity properties may exist levels, such that for the majority of the open for distinct connexins. What becomes im- time the conductive and permeation rates portant then, is determining if differential are dictated by the subconductive state, conductance values translate into vessel-spe- then this property of gap junction channels cific behaviors of the vascular wall, such as, would have very telling affects on tissue for example, propagated vasodilation or con- function. striction (21). Subconductive states: are they Table 1 - Unitary conductance of the four connexin physiologically relevant? types found in the vascular system.
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