Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the ?-adrenergic positive inotropic effect in human atrium

Grimm, Michael; Haas, Pascal; Willipinski-Stapelfeldt, Birthe; Zimmermann, Wolfram‐Hubertus; Rau, Thomas; Pantel, Klaus; Weyand, Michael; Eschenhagen, Thomas

doi:10.1016/j.cardiores.2004.09.019

Cited by 54 publications

(50 citation statements)

References 28 publications

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“…Since either pre-application of angiotensin II and endothelin-1 or antagonism of AT receptors largely reduced the atrial SFR, we propose that it is mediated by autocrine/paracrine release and action of these cardioactive peptides, similar to what has been found in ventricle of some animal species (Alvarez et al, 1999;Calaghan and White, 2001;Perez et al, 2001). In human atrium, G q -coupled receptors increase force via MLCK-dependent increases in the phosphorylation of MLC2a and increased myofilament Ca 2+ responsiveness (Grimm et al, 2005). Angiotensin II and endothelin-1 both act via G qcoupled receptors and we found clear evidence that the atrial SFR is mediated by MLCKdependent increases in MLC2a phosphorylation.…”

Section: Various Pathways and Mechanisms Contribute To The Stretch-insupporting

confidence: 66%

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The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

Kockskämper

Lewinski

Khafaga

et al. 2008

Progress in Biophysics and Molecular Biology

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Mechanical load is an important regulator of cardiac force. Stretching human atrial and ventricular trabeculae elicited a biphasic force increase: an immediate increase (Frank-Starling mechanism) followed by a further slow increase (slow force response, SFR). In ventricle, the SFR was unaffected by AT-and ET-receptor antagonism, by inhibition of protein-kinase-C, PI-3-kinase, and NOsynthase, but attenuated by inhibition of Na + /H + -(NHE) and Na + /Ca 2+ -exchange (NCX). In atrium, however, neither NHE-nor NCX-inhibition affected the SFR. Stretch elicited a large NHE-dependent [Na + ] i increase in ventricle but only a small, NHE-independent [Na + ] i increase in atrium. Stretchactivated non-selective cation channels contributed to basal force development in atrium but not ventricle and were not involved in the SFR in either tissue. Interestingly, inhibition of AT-receptors or pre-application of angiotensin II or endothelin-1 reduced the atrial SFR. Furthermore, stretch increased phosphorylation of atrial myosin light chain 2 (MLC2) and inhibition of myosin light chain kinase (MLCK) attenuated the SFR in atrium and ventricle. Thus, in human heart both atrial and ventricular myocardium exhibit a stretch-dependent SFR that might serve to adjust cardiac output to increased workload. In ventricle, there is a robust NHE-dependent (but angiotensin II-and endothelin-1-independent) [Na + ] i increase that is translated into a [Ca 2+ ] i and force increase via NCX. In atrium, on the other hand, there is an angiotensin II-and endothelin-dependent (but NHE-and NCX-independent) force increase. Increased myofilament Ca 2+ sensitivity through MLCK-induced phosphorylation of MLC2 is a novel mechanism contributing to the SFR in both atrium and ventricle.

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Section: Various Pathways and Mechanisms Contribute To The Stretch-insupporting

confidence: 66%

“…Immunoblotting of atrial myosin light chain 2 (MLC2a) was performed with antibodies against phosphorylated and total MLC2a as described before (Grimm et al, 2005;Grimm et al, 2006). Briefly, stretched and non-stretched muscle strips (n=36) were shock frozen in liquid nitrogen.…”

Section: Phosphorylation Of Myosin Light Chain 2amentioning

confidence: 99%

The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

Kockskämper

Lewinski

Khafaga

et al. 2008

Progress in Biophysics and Molecular Biology

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“…Other signalling pathways probably have a more prominent role 138 . For instance, α-adrenergic stimulation induced RLC phosphorylation in cardiac atria, although this effect was not observed in the ventricles 139 .…”

Section: Myosin Regulatory Chain Phosphorylationmentioning

confidence: 92%

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

111

122

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“…Wortmannin is another pharmacological inhibitor of MLCK that blocks phosphatidylinositol 3-kinase (PI3K) activity at a lower concentration (K i , 3 nM) (Arcaro and Wymann, 1993;Yano et al, 1995) and MLCK at a higher concentration (K i , 300 nM) (Nakanishi et al, 1992;Takayama et al, 1996;Sakurada et al, 1998;Qi et al, 2002;Grimm et al, 2005). Bath application of wortmannin (10 M) at a concentration that is sufficient to block both PI3K and MLCK, changed neither mEPSC frequency (supplemental Fig.…”

Section: Localization Of Mlck In Axonsmentioning

confidence: 99%

Myosin Light Chain Kinase Is Not a Regulator of Synaptic Vesicle Trafficking during Repetitive Exocytosis in Cultured Hippocampal Neurons

Tokuoka

Goda²

2006

J. Neurosci.

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The mechanism by which synaptic vesicles (SVs) are recruited to the release site is poorly understood. One candidate mechanism for trafficking of SVs is the myosin-actin motor system. Myosin activity is modulated by myosin light chain kinase (MLCK), which in turn is activated by calmodulin. Ca 2ϩ signaling in presynaptic terminals, therefore, may serve to regulate SV mobility along actin filaments via MLCK. Previous studies in different types of synapses have supported such a hypothesis. Here, we further investigated the role of MLCK in neurotransmitter release at glutamatergic synapses in cultured hippocampal neurons by examining the effects of two MLCK inhibitors, 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine⅐HCl (ML-7) and wortmannin. Bath application of ML-7 enhanced shortterm depression of EPSCs to repetitive stimulation, whereas it reduced presynaptic release probability. However, ML-7 also inhibited action potential amplitude and voltage-gated Ca 2ϩ channel currents. These effects were not mimicked by wortmannin, suggesting that ML-7 was not specific to MLCK in hippocampal neurons. When SV exocytosis was directly triggered by a Ca 2ϩ ionophore, calcimycin, to bypass voltage-gated Ca 2ϩ channels, ML-7 had no effect on neurotransmitter release. Furthermore, when SV exocytosis elicited by electrical field stimulation was monitored by styryl dye, FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide], the unloading kinetics of the dye was not altered in the presence of wortmannin. These data indicate that MLCK is not a major regulator of presynaptic SV trafficking during repetitive exocytosis at hippocampal synapses.

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Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the ?-adrenergic positive inotropic effect in human atrium

Abstract: alpha(1)-Adrenergic receptors mediate a prominent increase in contractile force in human atria that depends on MLCK activity and is accompanied by an increase in MLC2 phosphorylation.

Cited by 54 publications

References 28 publications

The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

Targeting the sarcomere to correct muscle function

Myosin Light Chain Kinase Is Not a Regulator of Synaptic Vesicle Trafficking during Repetitive Exocytosis in Cultured Hippocampal Neurons

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