scholarly journals Abnormal myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization contribute to impaired myogenic regulation of cerebral arterial diameter in the type 2 diabetic Goto-Kakizaki rat

2016 ◽  
Vol 37 (1) ◽  
pp. 227-240 ◽  
Author(s):  
Khaled S Abd-Elrahman ◽  
Olaia Colinas ◽  
Emma J Walsh ◽  
Hai-Lei Zhu ◽  
Christine M Campbell ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Light Chain ◽  
Actin Polymerization ◽  
Myosin Light Chain ◽  
Intraluminal Pressure ◽  
Myogenic Response ◽  
Myosin Phosphatase ◽  
Myosin Light Chain Phosphatase ◽  
Myogenic Regulation

The myogenic response of cerebral resistance arterial smooth muscle to intraluminal pressure elevation is a key physiological mechanism regulating blood flow to the brain. Rho-associated kinase plays a critical role in the myogenic response by activating Ca2+ sensitization mechanisms: (i) Rho-associated kinase inhibits myosin light chain phosphatase by phosphorylating its targeting subunit myosin phosphatase targeting subunit 1 (at T855), augmenting 20 kDa myosin regulatory light chain (LC20) phosphorylation and force generation; and (ii) Rho-associated kinase stimulates cytoskeletal actin polymerization, enhancing force transmission to the cell membrane. Here, we tested the hypothesis that abnormal Rho-associated kinase-mediated myosin light chain phosphatase regulation underlies the dysfunctional cerebral myogenic response of the Goto-Kakizaki rat model of type 2 diabetes. Basal levels of myogenic tone, LC20, and MYPT1-T855 phosphorylation were elevated and G-actin content was reduced in arteries of pre-diabetic 8–10 weeks Goto-Kakizaki rats with normal serum insulin and glucose levels. Pressure-dependent myogenic constriction, LC20, and myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization were suppressed in both pre-diabetic Goto-Kakizaki and diabetic (18–20 weeks) Goto-Kakizaki rats, whereas RhoA, ROK2, and MYPT1 expression were unaffected. We conclude that abnormal Rho-associated kinase-mediated Ca2+ sensitization contributes to the dysfunctional cerebral myogenic response in the Goto-Kakizaki model of type 2 diabetes.

scholarly journals The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

2012 ◽  
Vol 33 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Michael P Walsh ◽  
William C Cole
Keyword(s):  
Light Chain ◽  
Actin Polymerization ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Intraluminal Pressure ◽  
Regulatory Subunit ◽  
Myogenic Response ◽  
Force Transmission ◽  
Resistance Arteries

The myogenic response has a critical role in regulation of blood flow to the brain. Increased intraluminal pressure elicits vasoconstriction, whereas decreased intraluminal pressure induces vasodilatation, thereby maintaining flow constant over the normal physiologic blood pressure range. Improved understanding of the molecular mechanisms underlying the myogenic response is crucial to identify deficiencies with pathologic consequences, such as cerebral vasospasm, hypertension, and stroke, and to identify potential therapeutic targets. Three mechanisms have been suggested to be involved in the myogenic response: (1) membrane depolarization, which induces Ca2+ entry, activation of myosin light chain kinase, phosphorylation of the myosin regulatory light chains (LC20), increased actomyosin MgATPase activity, cross-bridge cycling, and vasoconstriction; (2) activation of the RhoA/Rho-associated kinase (ROCK) pathway, leading to inhibition of myosin light chain phosphatase by phosphorylation of MYPT1, the myosin targeting regulatory subunit of the phosphatase, and increased LC20 phosphorylation; and (3) activation of the ROCK and protein kinase C pathways, leading to actin polymerization and the formation of enhanced connections between the actin cytoskeleton, plasma membrane, and extracellular matrix to augment force transmission. This review describes these three mechanisms, emphasizing recent developments regarding the importance of dynamic actin polymerization in the myogenic response of the cerebral vasculature.

Abnormal Rho-associated kinase activity contributes to the dysfunctional myogenic response of cerebral arteries in type 2 diabetes

2015 ◽  
Vol 93 (3) ◽  
pp. 177-184 ◽  
Author(s):  
Khaled S. Abd-Elrahman ◽  
Michael P. Walsh ◽  
William C. Cole
Keyword(s):  
Type 2 Diabetes ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Kinase Activity ◽  
Cerebral Arteries ◽  
Myogenic Response ◽  
Resistance Arteries ◽  
Blood Brain Barrier Disruption ◽  
Myogenic Regulation

The structural and functional integrity of the brain, and therefore, cognition, are critically dependent on the appropriate control of blood flow within the cerebral circulation. Inadequate flow leads to ischemia, whereas excessive flow causes small vessel rupture and (or) blood–brain-barrier disruption. Cerebral blood flow is controlled through the interplay of several physiological mechanisms that regulate the contractile state of vascular smooth muscle cells (VSMCs) within the walls of cerebral resistance arteries and arterioles. The myogenic response of cerebral VSMCs is a key mechanism that is responsible for maintaining constant blood flow during variations in systemic pressure, i.e., flow autoregulation. Inappropriate myogenic control of cerebral blood flow is associated with, and prognostic of, neurological deterioration and poor outcome in patients with several conditions, including type 2 diabetes. Here, we review recent advances in our understanding of the role of inappropriate Rho-associated kinase activity as a cause of impaired myogenic regulation of cerebral arterial diameter in type 2 diabetes.

scholarly journals Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1)

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Joshua J Filter ◽  
Byron C Williams ◽  
Masumi Eto ◽  
David Shalloway ◽  
Michael L Goldberg
Keyword(s):  
Light Chain ◽  
Active Site ◽  
Slow Rate ◽  
Myosin Light Chain ◽  
Muscle Relaxation ◽  
Smooth Muscles ◽  
Unfair Competition ◽  
Myosin Phosphatase ◽  
Myosin Light Chain Phosphatase

The small phosphoprotein pCPI-17 inhibits myosin light-chain phosphatase (MLCP). Current models postulate that during muscle relaxation, phosphatases other than MLCP dephosphorylate and inactivate pCPI-17 to restore MLCP activity. We show here that such hypotheses are insufficient to account for the observed rapidity of pCPI-17 inactivation in mammalian smooth muscles. Instead, MLCP itself is the critical enzyme for pCPI-17 dephosphorylation. We call the mutual sequestration mechanism through which pCPI-17 and MLCP interact inhibition by unfair competition: MLCP protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from MLCP’s active site. MLCP dephosphorylates pCPI-17 at a slow rate that is, nonetheless, both sufficient and necessary to explain the speed of pCPI-17 dephosphorylation and the consequent MLCP activation during muscle relaxation.

scholarly journals Arachidonic acid inhibits myosin light chain phosphatase and sensitizes smooth muscle to calcium.

1992 ◽  
Vol 267 (30) ◽  
pp. 21492-21498
Author(s):  
M.C. Gong ◽  
A Fuglsang ◽  
D Alessi ◽  
S Kobayashi ◽  
P Cohen ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Myosin Light Chain Phosphatase
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