Role of myosin light chain kinase and myosin light chain phosphatase in the resistance arterial myogenic response to intravascular pressure

Cole, William C.; Welsh, Donald G.

doi:10.1016/j.abb.2011.02.024

Cited by 108 publications

(137 citation statements)

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“…First, it could play a 'direct' role in elevating the global concentration of cytosolic Ca 2+ . Such a rise would enhance tone development by augmenting myosin phosphorylation, a process tightly controlled by myosin light chain kinase and phosphatase (Gallagher et al, 1997;Cole and Welsh, 2011). The second possible mechanism focuses on a more 'indirect' role whereby Ca 2+ influx through T-type channels may locally regulate Ca 2+ -sensitive conductances that influence steady-state membrane potential.…”

Section: Functional Implicationsmentioning

confidence: 99%

“…Under dynamic conditions, tone within this network is regulated by multiple stimuli including changes in tissue metabolism (Harder et al, 1998;Filosa et al, 2006), humoral/neural stimuli (Furchgott and Zawadzki, 1980;Brayden and Bevan, 1985;Si and Lee, 2002), and intravascular pressure Segal, 2000). These stimuli influence tone by altering myosin light chain phosphorylation, a process controlled by global changes in cytosolic Ca 2+ (Davis, 1993;Gallagher et al, 1997;Cole and Welsh, 2011). Changes in cytosolic Ca 2+ concentration [Ca 2+ ] are principally set by resting membrane potential and steady state Ca 2+ influx through voltagegated Ca 2+ channels Welsh et al, 2000;Welsh et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase a regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle

Harraz

Welsh

2013

Journal of Cell Science

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Summary Recent investigations have identified that T-type Ca2+ channels (Ca V 3.x) are expressed in rat cerebral arterial smooth muscle. In the study reported here, we isolated the T-type conductance, differentiated the current into the Ca V 3.1/Ca V 3.2 subtypes and determined whether they are subject to protein kinase regulation. Using patch clamp electrophysiology, whole-cell Ba 2+ current was monitored and initially subdivided into nifedipine-sensitive and -insensitive components. The latter conductance was abolished by T-type Ca 2+ channel blockers and was faster with leftward shifted activation/inactivation properties, reminiscent of a T-type channel. Approximately 60% of this T-type conductance was blocked by 50 mM Ni 2+ , a concentration that selectively interferes with Ca V 3.2 channels. Subsequent work revealed that the whole-cell T-type conductance was subject to protein kinase A (PKA) modulation. Specifically, positive PKA modulators (db-cAMP, forskolin, isoproterenol) suppressed T-type currents and evoked a hyperpolarized shift in steady-state inactivation. Blocking PKA (with KT5720) masked this suppression without altering the basal T-type conductance. A similar effect was observed with stHt31, a peptide inhibitor of A-kinase anchoring proteins. A final set of experiments revealed that PKA-induced suppression targeted the Ca V 3.2 subtype. In summary, this study revealed that a T-type Ca 2+ channel conductance can be isolated in arterial smooth muscle, and differentiated into Ca V 3.1 and Ca V 3.2 components. It also showed that vasodilatory signaling cascades inhibit this conductance by targeting Ca V 3.2. Such targeting would impact Ca 2+ dynamics and consequent tone regulation in the cerebral circulation.

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Section: Functional Implicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein kinase a regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle

Harraz

Welsh

2013

Journal of Cell Science

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“…Finally, MYPT1 acts as a scaffold for other proteins including Par-4, HSP27, and M-RIP (25). Thus, MYPT1 appears to play a central role in regulating MLCP activity through direct interactions with PP1c␦, its phosphorylation by different kinases, and its actions as a scaffold for other proteins that may affect RLC phosphorylation (8,11,14,25).…”

mentioning

confidence: 99%

“…Vascular tone is regulated via G-protein-coupled receptors (GPCRs) acting on two major signaling modules involving the heterotrimeric G proteins G q /G 11 and G 12 /G 13 . G q /G 11 mediates the activation of phospholipase C to generate inositol 1,4,5-trisphosphate, which releases Ca 2ϩ from the sarcoplasmic reticulum, leading to Ca 2ϩ /calmodulin-dependent activation of myosin light chain kinase (7)(8)(9). The G 12 /G 13 proteins couple to Rho guanine nucleotide exchange factor (RhoGEF) proteins to activate RhoA and thereby enhance the Ca 2ϩ -dependent contraction via RhoA kinase-dependent inhibition of myosin light chain phosphatase (MLCP) 3 (Ca 2ϩ -sensitization).…”

mentioning

confidence: 99%

Myosin Phosphatase Target Subunit 1 (MYPT1) Regulates the Contraction and Relaxation of Vascular Smooth Muscle and Maintains Blood Pressure

Qiao

Chen

et al. 2014

Journal of Biological Chemistry

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Background: MYPT1 is a regulatory subunit of myosin phosphatase. Results: Deleting MYPT1 in vascular smooth muscle enhances myosin phosphorylation, contractility, and blood pressure. Conclusion: Genetic evidence shows MYPT1 plays a role in modulating vascular smooth muscle contractility. Significance: Although MYPT1 is not essential for vascular smooth muscle contractility, it contributes to blood pressure maintenance in vivo through signaling to myosin phosphorylation.

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“…It is accepted that phosphorylation of MLC in smooth muscle is required to initiate actomyosin interaction (Kamm and Stull, 1985;Murthy, 2006;Cole and Welsh, 2011). Because MLCK and MLCP are physically associated with the contractile units, it is reasonable to assume that within the contractile units myosin motors are well regulated by these enzymes, i.e.…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle function and myosin polymerization

Chitano

Wang

Tin

et al. 2017

Journal of Cell Science

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Smooth muscle is able to function over a much broader length range than striated muscle. The ability to maintain contractility after a large length change is thought to be due to an adaptive process involving restructuring of the contractile apparatus to maximize overlap between the contractile filaments. The molecular mechanism for the length-adaptive behavior is largely unknown. In smooth muscle adapted to different lengths we quantified myosin monomers, basal and activation-induced myosin light chain (MLC) phosphorylation, shortening velocity, power output and active force. The muscle was able to generate a constant maximal force over a two fold length range when it was allowed to go through isometric contraction/relaxation cycles after each length change (length adaptation). In the relaxed state, myosin monomer concentration and basal MLC phosphorylation decreased linearly, while in the activated state activation-induced MLC phosphorylation and shortening velocity/power output increased linearly with muscle length. The results suggest that recruitment of myosin monomers and oligomers into the actin filament lattice (where they form force-generating filaments) occurs during muscle adaptation to longer length, with the opposite occurring during adaptation to shorter length.

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Role of myosin light chain kinase and myosin light chain phosphatase in the resistance arterial myogenic response to intravascular pressure

Cited by 108 publications

References 184 publications

Protein kinase a regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle

Protein kinase a regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle

Myosin Phosphatase Target Subunit 1 (MYPT1) Regulates the Contraction and Relaxation of Vascular Smooth Muscle and Maintains Blood Pressure

Smooth muscle function and myosin polymerization

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