The presence of Na+ channels in myometrial smooth muscle cells is revealed by specific neurotoxins

Amédée, Thierry; Renaud, Jean‐François; Jmari, K; Lombet, Alain; Mironneau, Jean; Lazdunski, Michel

doi:10.1016/0006-291x(86)91131-9

Cited by 33 publications

(6 citation statements)

References 18 publications

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“…APs generated in isolated cells in the current clamp mode were inhibited by 1 μ m TTX, which was also found to reduce membrane excitability by causing hyperpolarization. This was similar to findings by Amédée et al (1986), Muraki et al (1991) and Hollywood et al (1997) who all showed that evoked APs were blocked by TTX, although the former two required excessively high concentrations of TTX (10 μ m ). However, unlike Hollywood et al (1997) the mouse PV cells' AP was also abolished by an L‐type Ca 2+ channel blocker (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…In contrast to their established role in neurones, cardiomyocytes and skeletal muscle cells, voltage‐gated Na + channels are not thought to play a role in the contractility of smooth muscle, where membrane depolarization and any subsequent contraction are principally governed by the opening of voltage‐dependent Ca 2+ channels (VDCCs). Whilst there has been no convincing evidence to contradict this view, there are a number of electrophysiological studies that show that voltage‐gated Na + currents are present in smooth muscle cells (SMCs) including rat myometrium (Amédée et al 1986), rat portal vein (Mironneau et al 1990), neonatal azygous vein (Sturek & Hermsmeyer, 1986), guinea pig ureter (Muraki et al 1991), sheep lymphatics (Hollywood et al 1997) and rat vas deferens (Belevych et al 1999). However, the paucity of studies on this conductance in SMCs means that there is little information on its functional role.…”

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confidence: 99%

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Electrophysiological and molecular identification of voltage‐gated sodium channels in murine vascular myocytes

Saleh

Yeung

Prestwich

et al. 2005

The Journal of Physiology

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A voltage-gated Na + current was characterised in freshly dissociated mouse portal vein (PV) smooth muscle myocytes. The current was found superimposed upon the relatively slow L-type Ca 2+ current and was resistant to conventional Ca 2+ channel blockers but was abolished by external Na + replacement and tetrodotoxin (TTX, 1 µM). The molecular identity of the channel responsible for this conductance was determined by RT-PCR where only the transcripts for Na + channel genes SCN7a, 8a and 9a were detected. The presence of the protein counterparts to the SCN8a and 9a genes (NaV 1.6 and NaV 1.7 , respectively) on the individual smooth muscle myocytes were confirmed in immunocytochemistry, which showed diffuse staining around a predominantly plasmalemmal location. TTX inhibited the action potential in individual myocytes generated in the current clamp mode but isometric tissue tension experiments revealed that TTX (1 and 5 µM) had no effect on the inherent mouse PV rhythmicity. However, the Na + channel opener veratridine (10 and 50 µM) significantly increased the length of contraction and the interval between contractions. This effect was not influenced by pre-incubation with atropine, prazosin and propranolol, but was reversed by TTX (1 µM) and completely abolished by nicardipine (1 µM). Furthermore, preincubation with the reverse-mode Na + -Ca 2+ exchange blocker KB-R7943 (10 µM) also inhibited the veratridine response. We have established for the first time the molecular identity of the voltage-gated Na + channel in freshly dispersed smooth muscle cells and have shown that these channels can modulate contractility through a novel mechanism of action possibly involving reverse mode Na + -Ca 2+ exchange.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

Electrophysiological and molecular identification of voltage‐gated sodium channels in murine vascular myocytes

Saleh

Yeung

Prestwich

et al. 2005

The Journal of Physiology

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“…Some cultured cells had no inward currents at all ( Toro et al, 1990 ). In cultured cells, I Na could be elicited only after interference with Na + inactivation; when elicited, the K d of TTX blockade was 2 μM ( Amedee et al, 1986 ), characterizing the receptor as a low affinity type. The different TTX sensitivities could reflect different amino acid compositions of the channel molecules.…”

Section: Discussionmentioning

confidence: 99%

Sodium and Calcium Inward Currents in Freshly Dissociated Smooth Myocytes of Rat Uterus

Yamada

Wang

Kao

1997

The Journal of General Physiology

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Freshly dissociated myocytes from nonpregnant, pregnant, and postpartum rat uteri have been studied with the tight-seal patch-clamp method. The inward current contains both INa and ICa that are vastly different from those in tissue-cultured material. INa is abolished by Na+-free medium and by 1 μM tetrodotoxin. It first appears at ∼−40 mV, reaches maximum at 0 mV, and reverses at 84 mV. It activates with a voltage-dependent τ of 0.2 ms at 20 mV, and inactivates as a single exponential with a τ of 0.4 ms. Na+ conductance is half activated at −21.5 mV, and half inactivated at −59 mV. INa reactivates with a τ of 20 ms. ICa is abolished by Ca2+-free medium, Co2+ (5 mM), or nisoldipine (2 μM), and enhanced in 30 mM Ca2+, Ba2+, or BAY-K 8644. It first appears at ∼−30 mV and reaches maximum at +10 mV. It activates with a voltage-dependent τ of 1.5 ms at 20 mV, and inactivates in two exponential phases, with τ's of 33 and 133 ms. Ca2+ conductance is half activated at −7.4 mV, and half inactivated at −34 mV. ICa reactivates with τ's of 27 and 374 ms. INa and ICa are seen in myocytes from nonpregnant estrus uteri and throughout pregnancy, exhibiting complex changes. The ratio of densities of peak INa/ICa changes from 0.5 in the nonpregnant state to 1.6 at term. The enhanced role of INa, with faster kinetics, allows more frequent repetitive spike discharges to facilitate simultaneous excitation of the parturient uterus. In postpartum, both currents decrease markedly, with INa vanishing from most myocytes. Estrogen-enhanced genomic influences may account for the emergence of INa, and increased densities of INa and ICa as pregnancy progresses. Other influences may regulate varied channel expression at different stages of pregnancy.

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“…Evidence has shown that, in vascular smooth muscle, action potentials are not dependent on Na + channels since tetrodotoxin (TTX) has no effect on amplitude and duration of action potentials [18], leading to the belief that these channels might not be present or prominent in these tissues. Nonetheless, Na + currents (I Na ) have been measured in visceral smooth muscles such as myometrium and uterus (pregnant), colon, esophagus, stomach, and ureter as well as in certain vascular smooth muscles such as the portal and azygos veins [2,8,[24][25][26]31,33,34]. The identification of functional voltage-gated Na + channels in quiescent and proliferating vascular smooth muscle cells (VSMC), however, has not been as forthcoming.…”

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Identification of functional voltage-gated Na+ channels in cultured human pulmonary artery smooth muscle cells

Platoshyn

Remillard

Fantozzi

et al. 2005

Pflugers Arch - Eur J Physiol

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Electrical excitability, which plays an important role in excitation-contraction coupling in the pulmonary vasculature, is regulated by transmembrane ion flux in pulmonary artery smooth muscle cells (PASMC). This study aimed to characterize the electrophysiological properties and molecular identities of voltage-gated Na + channels in cultured human PASMC. We recorded tetrodotoxinsensitive and rapidly inactivating Na + currents with properties similar to those described in cardiac myocytes. Using RT-PCR, we detected transcripts of seven Na + channel α genes (SCN2A, 3A, 4A, 7A, 8A, 9A, and 11A), and two β subunit genes (SCN1B and 2B). Our results demonstrate that human PASMC express TTX-sensitive voltage-gated Na + channels. Their physiological functions remain unresolved, although our data suggest that Na + channel activity does not directly influence membrane potential, intracellular Ca 2+ release, or proliferation in normal human PASMC. Whether their expression and/or activity are heightened in the pathological state is discussed.Keywords membrane potential; Na + channels; vascular smooth muscle; pulmonary Voltage-gated Na + channels play a major role in regulating cell excitability, particularly as it pertains to the generation of action potentials in neurons, skeletal muscle, and cardiac myocytes. Evidence has shown that, in vascular smooth muscle, action potentials are not dependent on Na + channels since tetrodotoxin (TTX) has no effect on amplitude and duration of action potentials [18], leading to the belief that these channels might not be present or prominent in these tissues. Nonetheless, Na + currents (I Na ) have been measured in visceral smooth muscles such as myometrium and uterus (pregnant), colon, esophagus, stomach, and ureter as well as in certain vascular smooth muscles such as the portal and azygos veins [2,8,[24][25][26]31,33,34]. The identification of functional voltage-gated Na + channels in quiescent and proliferating vascular smooth muscle cells (VSMC), however, has not been as forthcoming. Currently, I Na have been measured in smooth muscle cells isolated from the coronary artery, aorta, vena cava, and pulmonary artery of various species, including humans [5,16,23,27]. On only rare occasions have I Na been recorded in freshly dissociated human VSMC, although they are readily detected when the same cells are cultured [28]. In isolated cases, I Na have been recorded in both freshly dispersed rabbit [27] de-differentiation and proliferation [28]. More specifically, voltage-gated Na + channel expression and activity may be required either to facilitate the transition or to promote the de-differentiation of cells from "contractile" to "synthetic" or "proliferative" phenotypes [20,30]. This raises the possibility that the expression of functional voltage-gated Na + channels in cultured cells act as a trigger for cell de-differentiation and proliferation, possibly via enhanced cytoplasmic free Ca 2+ concentration ([Ca 2+ ] cyt ).The molecular identification of the subunits that make ...

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The presence of Na+ channels in myometrial smooth muscle cells is revealed by specific neurotoxins

Cited by 33 publications

References 18 publications

Electrophysiological and molecular identification of voltage‐gated sodium channels in murine vascular myocytes

Electrophysiological and molecular identification of voltage‐gated sodium channels in murine vascular myocytes

Sodium and Calcium Inward Currents in Freshly Dissociated Smooth Myocytes of Rat Uterus

Identification of functional voltage-gated Na+ channels in cultured human pulmonary artery smooth muscle cells

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