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            Ion Activation and Inactivation of the Ventricular Gap Junction

Swietach, Pawel; Rossini, Alessandra; Spitzer, Kenneth W.; Vaughan‐Jones, Richard D.

doi:10.1161/01.res.0000264071.11619.47

Cited by 37 publications

(22 citation statements)

References 40 publications

(94 reference statements)

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“…The sole exception is that of sCx35 junctions, which clearly show a biphasic pH dependence since their conductance also decreases following acidosis, albeit in a less pronounced manner than after alkalosis. Recently, this kind of dual pH sensitivity has also been observed in the gap junctions of cardiac myocytes (29). In previous studies in vitro, wherein the effect of alkalization was not explored and the experiments were carried out without measuring the pH i , a partial uncoupling effect of acidosis on sCx35 was also observed (22).…”

Section: Discussionmentioning

confidence: 91%

Regulation of neuronal connexin-36 channels by pH

González‐Nieto

Gómez‐Hernández

Larrosa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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Neurotransmission through electrical synapses plays an important role in the spike synchrony among neurons and oscillation of neuronal networks. Indeed, electrical transmission has been implicated in the hypersynchronous electrical activity of epilepsy. We have investigated the influence of intracellular pH on the strength of electrical coupling mediated by connexin36 (Cx36), the principal gap junction protein in the electrical synapses of vertebrates. In striking contrast to other connexin isoforms, the activity of Cx36 channels decreases following alkalosis rather than acidosis when it is expressed in Xenopus oocytes and N2A cells. This uncoupling of Cx36 channels upon alkalinization occurred in the vertebrate orthologues analyzed (human, mouse, chicken, perch, and skate). While intracellular acidification caused a mild or moderate increase in the junctional conductance of virtually all these channels, the coupling of the skate Cx35 channel was partially blocked by acidosis. The mutational analysis suggests that the Cx36 channels may contain two gating mechanisms operating with opposing sensitivity to pH. One gate, the dominant mechanism, closes for alkalosis and it probably involves an interaction between the Cand N-terminal domains, while a secondary acid sensing gate only causes minor, albeit saturating, changes in coupling following acidosis and alkalosis. Thus, we conclude that neuronal Cx36 channels undergo unique regulation by pH i since their activity is inhibited by alkalosis rather than acidosis. These data provide a novel basis to define the relevance and consequences of the pH-dependent modulation of Cx36 synapses under physiological and pathological conditions. alkalosis ͉ electrical synapses ͉ intracellular pH ͉ pH gating ͉ gap junction

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Section: Discussionmentioning

confidence: 91%

Regulation of neuronal connexin-36 channels by pH

González‐Nieto

Gómez‐Hernández

Larrosa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Depending on the predominating mechanism, ICWs can be inhibited (240) or stimulated (341) by low extracellular Ca 2ϩ conditions (TABLE 3). Acidosis is generally believed to inhibit gap junctions (334), but it may also have an opposite effect (356). Hemichannels are also inhibited by acidosis (304,375) and opened with alkalosis (315).…”

Section: A Inhibitors Of Gap Junction Couplingmentioning

confidence: 99%

Intercellular Ca²⁺Waves: Mechanisms and Function

Leybaert

Sanderson

2012

Physiological Reviews

275

290

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Intercellular calcium (Ca 2ϩ ) waves (ICWs) represent the propagation of increases in intracellular Ca 2ϩ through a syncytium of cells and appear to be a fundamental mechanism for coordinating multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca 2ϩ from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra-and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiological functions of ICWs.

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“…Coupling is attained by gap junctions formed by connexins, such as Cx43 (product of GJA1). The diffusive transport of H + ions through gap junctions and across the syncytium is facilitated by mobile buffers (29), which are present in stromal cytoplasm. Because stromal cytoplasmic carbonic anhydrase activity is low (33), the majority of H + traffic is carried aboard membrane-impermeant (intrinsic) buffers rather than by membrane-permeant CO 2 /HCO 3 − , and is consequently routed through the syncytial cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated an acute effect of pH i on cell-to-cell coupling (29,30). To test whether acidification uncouples the stromal syncytium, FRAP experiments were repeated on NHDF-Ad and InMyoFib monolayers equilibrated (>10 min) with acidic media.…”

Section: Cell-to-cell Transmission Of Acid Through Gap Junctions Is Hmentioning

confidence: 99%

“…The highly buffered milieu inside cells hinders the movement of free H + ions; therefore, the transmission of acid between cells relies on H + ions being chaperoned aboard mobile (diffusible) H + buffers (29,31). These buffers include CO 2 /HCO 3 − and "intrinsic" molecules, such as amino acids, peptides, and phosphates.…”

Section: Cell-to-cell Transmission Of Acid Through Gap Junctions Is Hmentioning

confidence: 99%

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Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid

Hulı́ková

Black

Hsia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Proliferation and invasion of cancer cells require favorable pH, yet potentially toxic quantities of acid are produced metabolically. Membrane-bound transporters extrude acid from cancer cells, but little is known about the mechanisms that handle acid once it is released into the poorly perfused extracellular space. Here, we studied acid handling by myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDF-Ad), and colorectal cancer (CRC) cells (HCT116, HT29) grown in monoculture or coculture. Expression of the acidloading transporter anion exchanger 2 (AE2) (SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared with CRC cells, Hs675.T and InMyoFib myofibroblasts had very high capacity to absorb extracellular acid. Acid uptake into CCD-112-CoN and NHDF-Ad cells was slower and comparable to levels in CRC cells, but increased alongside SLC4A2 expression under stimulation with transforming growth factor β1 (TGFβ1), a cytokine involved in cancer-stroma interplay. Myofibroblasts and fibroblasts are connected by gap junctions formed by proteins such as connexin-43, which allows the absorbed acid load to be transmitted across the stromal syncytium. To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGFβ1. In contrast, acid transmission was absent between CRC cells, even after treatment with TGFβ1. Thus, stromal cells have the necessary molecular apparatus for assembling an acidventing route that can improve the flow of metabolic acid through tumors. Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities.colorectal cancer | myofibroblast | anion exchanger 2 | gap junctions | TGFβ1

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H ⁺ Ion Activation and Inactivation of the Ventricular Gap Junction

Cited by 37 publications

References 40 publications

Regulation of neuronal connexin-36 channels by pH

Regulation of neuronal connexin-36 channels by pH

Intercellular Ca²⁺Waves: Mechanisms and Function

Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid

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H + Ion Activation and Inactivation of the Ventricular Gap Junction

Cited by 37 publications

References 40 publications

Regulation of neuronal connexin-36 channels by pH

Regulation of neuronal connexin-36 channels by pH

Intercellular Ca2+Waves: Mechanisms and Function

Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid

Contact Info

Product

Resources

About

H ⁺ Ion Activation and Inactivation of the Ventricular Gap Junction

Intercellular Ca²⁺Waves: Mechanisms and Function