Ca2+ clearance in smooth muscle: lessons from gene-altered mice

Ishida, Yukisato; Rutgeerts, Paul

doi:10.1540/jsmr.41.235

Cited by 27 publications

(34 citation statements)

References 59 publications

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“…Mitochondria are also included, though their role in Ca 2+ -clearance is not known with certainty. Adapted from Ishida and Paul [2]. Experimental records showing the Ca 2+ signal (upper trace in each panel) and simultaneously recorded isometric force (lower trace in each panel) of bladder smooth muscle from Pmca1 +/-and Pmca4 -/-mice.…”

Section: Summary and Beyondmentioning

confidence: 99%

“…Thus Ca 2+ clearance from the cytosol is critical to the maintenance of a quiescent baseline and is a major factor in modulation of Ca 2+ homeostasis and thus contractile force. The plasma membrane Ca 2+ ATPase (PMCA), sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA), Na + -Ca 2+ -exchanger (NCX) and mitochondria all function to some extent in this process (for reviews see [2,3]). Figure 1 shows a schematic illustration of these Ca 2+ clearance pathways.…”

mentioning

confidence: 99%

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Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Oloizia

Rutgeerts

2008

Journal of Molecular and Cellular Cardiology

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The central importance of calcium clearance proteins, and their regulators, in the modulation of myocardial contractility and intracellular Ca 2+ concentration ([Ca 2+ ] i ) has long been established. Key players identified include the Na + -Ca 2+ exchanger, the Na + -K + ATPase, the sarco(endo)plasmic reticulum Ca 2+ -ATPase and associated phospholamban. Gene-targeted and transgenic murine models have been critical in the elucidation of their function. The study of these proteins in the regulation of contractile parameters in vascular smooth muscle, on the other hand, is less well studied. More recently, gene-targeted and transgenic models have expanded our knowledge of Ca 2+ clearance proteins and their role in both tonic and phasic smooth muscle contractility. In this review, we will briefly treat the mechanisms which underlie Ca 2+ clearance in smooth muscle. These will be addressed in light of studies using gene-modified mouse models, the results of which will be compared and contrasted with those in the cardiomyocyte. The recently identified human mutations in phospholamban, which lead to dilated cardiomyopathy, are also present in vascular and other smooth muscle. Given the importance of these Ca 2+ clearance systems to modulation of smooth muscle, it is likely that mutations will also lead to smooth muscle pathology. Ca 2+ CLEARANCE AND REGULATION OF [Ca 2+ ] iCa 2+ homeostasis is central to the regulation of smooth muscle function. It is well established that [Ca 2+ ] i plays an essential role in the activation of myosin light chain kinase, which phosphorylates myosin, thereby activating the actin-myosin interaction (for review see [1]). It has also be estimated that Ca 2+ influx under basal conditions is 16 μmole/liter per minute, more than 2 orders of magnitude greater than the resting [Ca 2+ ] i . Thus Ca 2+ clearance from the cytosol is critical to the maintenance of a quiescent baseline and is a major factor in modulation of Ca 2+ homeostasis and thus contractile force. The plasma membrane Ca 2+ ATPase (PMCA), sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA), Na + -Ca 2+ -exchanger (NCX) and mitochondria all function to some extent in this process (for reviews see [2,3]). Figure 1 shows a schematic illustration of these Ca 2+ clearance pathways. Also of importance to smooth muscle Ca 2+ clearance are phospholamban (PLN), an endogenous inhibitor of SERCA, and the Na + -K + ATPase (NKA), which couples to NCX, and facilitates the extrusion of Ca 2+ via the forward mode of the exchanger. NCX is generally considered to be a high-capacity exchanger, i.e., low affinity for Ca 2+ (K d ≈1 μM), but high turnover [4][5][6][7]. SERCA and PMCA, on the other hand, have a higher affinity for Ca 2+ (K d ≈0.1-0.3 μM) [6,[8][9][10][11], but lower turnover than NCX. For smooth muscle, the relative contribution of each to Ca 2+ clearance is dependent on conditions and smooth muscle type, but in general, NCX accounts for about 60%, while PMCA and Publisher's Disclaimer: This is a PDF file of an unedited manu...

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Section: Summary and Beyondmentioning

confidence: 99%

mentioning

confidence: 99%

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Oloizia

Rutgeerts

2008

Journal of Molecular and Cellular Cardiology

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“…smooth muscle and ICC, it is not lost from the plasmalemma in caveolin 1 knockout [40][41][42]. There are several isoforms of the PMCA and the PMCA 4 isoforms that are important in smooth muscle [54][55][56][57]. In the absence of caveolins, PMCA remains, perhaps located in the lipid raft component.…”

Section: Functional Experimentsmentioning

confidence: 99%

“…This exchanger can also be manipulated by modifying the Na gradient which drives forward exchange [57] or the Ca 2+ gradient which can drive reverse exchange [46].…”

Section: Functional Experimentsmentioning

confidence: 99%

Caveolae and calcium handling, a review and a hypothesis

Daniel

El‐Yazbi

Cho

2006

Journal of Cellular and Molecular Medicine

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Caveolae are associated with molecules crucial for calcium handling. This review considers the roles of caveolae in calcium handling for smooth muscle and interstitial cells of Cajal (ICC). Structural studies showed that the plasma membrane calcium pump (PMCA), a sodium-calcium exchanger (NCX1), and a myogenic nNOS appear to be colocalized with caveolin I, the main constituent of these caveolae. Voltage dependent calcium channels (VDCC) are associated but not co-localized with caveolin 1, as are proteins of the peripheral sarcoplasmic reticulum (SR) such as calreticulin. Only the nNOS is absent from caveolin 1 knockout animals. Functional studies in calcium free media sugest that a source of calcium in tonic smooth muscles exists, partly sequestered from extracellular EGTA. This source supported sustained contractions to carbachol using VDCC and dependent on activity of the SERCA pump. This source is postulated to be caveolae, near peripheral SR. New evidence, presented here, suggests that a similar source exists in phasic smooth muscle of the intestine and its ICC. These results suggest that caveolae and peripheral SR are a functional unit recycling calcium through VDCC and controlling its local concentration. Calcium handling molecules associated with caveolae in smooth muscle and ICC were identified and their possible functions also reviewed.

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“…Increases in VSM [Ca 2ϩ ] i are triggered by influxes of Ca 2ϩ through several plasma membrane Ca 2ϩ channels and by release of Ca 2ϩ from stores (6,7,35). Conversely, [Ca 2ϩ ] i is reduced by Ca 2ϩ extrusion via plasma membrane Ca 2ϩ ATPase (PMCA) and NCX and through sequestration of Ca 2ϩ in the sarcoplasmic reticulum (SR) via sarcoplasmic/endoplasmic Ca 2ϩ ATPase (SERCA) (14). Although less information is available about the effects of membrane depolarization on Ca 2ϩ sequestration (SERCA) and extrusion (PMCA or NCX), it is known that inhibition of NCX increases the membrane potential and elevates [Ca 2ϩ ] i (22).…”

mentioning

confidence: 99%

Mechanism of glucose-6-phosphate dehydrogenase-mediated regulation of coronary artery contractility

Ata

Rawat²,

Lincoln

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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We previously identified glucose-6-phosphate dehydrogenase (G6PD) as a regulator of vascular smooth muscle contraction. In this study, we tested our hypothesis that G6PD activated by KCl via a phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-protein kinase C (PKC) pathway increases vascular smooth muscle contraction and that inhibition of G6PD relaxes smooth muscle by decreasing intracellular Ca(2+) ([Ca(2+)](i)) and Ca(2+) sensitivity to the myofilament. Here we show that G6PD is activated by membrane depolarization via PKC and PTEN pathway and that G6PD inhibition decreases intracellular free calcium ([Ca(2+)](i)) in vascular smooth muscle cells and thus arterial contractility. In bovine coronary artery (CA), KCl (30 mmol/l) increased PKC activity and doubled G6PD V(max) without affecting K(m). KCl-induced PKC and G6PD activation was inhibited by bisperoxo(pyridine-2-carboxyl)oxovanadate (Bpv; 10 μmol/l), a PTEN inhibitor, which also inhibited (P < 0.05) KCl-induced CA contraction. The G6PD blockers 6-aminonicotinamide (6AN; 1 mmol/l) and epiandrosterone (EPI; 100 μmol/l) inhibited KCl-induced increases in G6PD activity, [Ca(2+)](i), Ca(2+)-dependent myosin light chain (MLC) phosphorylation, and contraction. Relaxation of precontracted CA by 6AN and EPI was not blocked by calnoxin (10 μmol/l), a plasma membrane Ca(2+) ATPase inhibitor or by lowering extracellular Na(+), which inhibits the Na(+)/Ca(2+) exchanger (NCX), but cyclopiazonic acid (200 μmol/l), a sarcoplasmic reticulum Ca(2+) ATPase inhibitor, reduced (P < 0.05) 6AN- and EPI-induced relaxation. 6AN also attenuated phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Ser855, a site phosphorylated by Rho kinase, inhibition of which reduced (P < 0.05) KCl-induced CA contraction and 6AN-induced relaxation. By contrast, 6AN increased (P < 0.05) vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser239, indicating that inhibition of G6PD increases PKA or PKG activity. Inhibition of PKG by RT-8-Br-PET-cGMPs (100 nmol/l) diminished 6AN-evoked VASP phosphorylation (P < 0.05), but RT-8-Br-PET-cGMPs increased 6AN-induced relaxation. These findings suggest G6PD inhibition relaxes CA by decreasing Ca(2+) influx, increasing Ca(2+) sequestration, and inhibiting Rho kinase but not by increasing Ca(2+) extrusion or activating PKG.

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Ca2+ clearance in smooth muscle: lessons from gene-altered mice

Abstract: Abstract

Cited by 27 publications

References 59 publications

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Caveolae and calcium handling, a review and a hypothesis

Mechanism of glucose-6-phosphate dehydrogenase-mediated regulation of coronary artery contractility

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