Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction

Gunst, Susan J.; Zhang, Wenwu

doi:10.1152/ajpcell.00253.2008

Cited by 323 publications

(400 citation statements)

References 151 publications

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“…How the functional phenotypes in myofibroblasts translate to aortic smooth muscle needs to be considered in light of the roles of actin in vascular smooth muscle where it is critical for force production and maintenance of the submembrane cytoskeleton that strengthens connections between contractile proteins and the extracellular matrix (13). Additionally, actin plays an important role in modulating transcription of vascular muscle contractile protein genes via its interaction with MRTF-A.…”

Section: Discussionmentioning

confidence: 99%

“…Filamentous actin (F-actin) arises from the polymerization of monomeric globular actin (G-actin). F-actin supports force production through its interaction with myosin filaments, and it supports force transmission via the actin cytoskeleton that stabilizes adhesive structures connected to the elastin-extracellular matrix (13). Dissected aortas exhibit characteristic features, including loss and disarray of smooth muscle cells in the medial layer, loss of elastic fibers, and proteoglycan accumulation in the medial space (4).…”

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confidence: 99%

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Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have demonstrated that the polymerization of a small pool of actin during contractile activation is necessary for agonist-induced tension generation in airway smooth muscle, and this actin polymerization can be inhibited without affecting stimulus-induced MLC phosphorylation (16,38,64). In the present study, we found that the inhibitory effects of RhoA activation on myosin light chain phosphatase contributed to the increase in MLC phosphorylation induced by ACh; however, this effect was small in the airway smooth muscle tissues and did not contribute significantly to overall tension generation.…”

Section: Discussionmentioning

confidence: 99%

“…Both processes are necessary for tension development in tracheal smooth muscle as well as in a number of other types of smooth muscle tissues (3,16,29,61,63). Studies of airway smooth muscle and some other types of smooth muscle have shown that the treatment of smooth muscle tissues with pharmacologic or molecular inhibitors of actin polymerization have little or no effect on the increase in MLC phosphorylation induced by contractile stimulation, which suggests that the actin polymerization does not regulate contraction by contributing to processes that modulate MLC phosphorylation and cross-bridge cycling (16, 38, 42, 43, 49, 51, 57-59, 64, 65).…”

Section: Discussionmentioning

confidence: 99%

“…Contractile agonists have been shown to stimulate actin polymerization in a number of smooth muscle cells and tissues, and the critical role of actin polymerization in regulating active tension development in smooth muscle is well documented (4,8,12,16,18,22,29,38,63,64,67). The inhibition of actin polymerization using either pharmacologic or molecular approaches has been shown to depress tension development in many smooth muscles with little or no effect on MLC phosphorylation or cross-bridge cycling (16, 38, 42, 43, 49, 51, 57-59, 64, 65).…”

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The effects of the small GTPase RhoA on the muscarinic contraction of airway smooth muscle result from its role in regulating actin polymerization

Zhang

Gunst

2010

American Journal of Physiology-Cell Physiology

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Zhang W, Du L, Gunst SJ. The effects of the small GTPase RhoA on the muscarinic contraction of airway smooth muscle result from its role in regulating actin polymerization. Am J Physiol Cell Physiol 299: C298 -C306, 2010. First published May 5, 2010 doi:10.1152/ajpcell.00118.2010.-The small GTPase RhoA increases the Ca 2ϩ sensitivity of smooth muscle contraction and myosin light chain (MLC) phosphorylation by inhibiting the activity of MLC phosphatase. RhoA is also a known regulator of cytoskeletal dynamics and actin polymerization in many cell types. In airway smooth muscle (ASM), contractile stimulation induces MLC phosphorylation and actin polymerization, which are both required for active tension generation. The objective of this study was to evaluate the primary mechanism by which RhoA regulates active tension generation in intact ASM during stimulation with acetylcholine (ACh). RhoA activity was inhibited in canine tracheal smooth muscle tissues by expressing the inactive RhoA mutant, RhoA T19N, in the intact tissues or by treating them with the cell-permeant RhoA inhibitor, exoenzyme C3 transferase. RhoA inactivation reduced ACh-induced contractile force by ϳ60% and completely inhibited ACh-induced actin polymerization but inhibited ACh-induced MLC phosphorylation by only ϳ20%. Inactivation of MLC phosphatase with calyculin A reversed the reduction in MLC phosphorylation caused by RhoA inactivation, but calyculin A did not reverse the depression of active tension and actin polymerization caused by RhoA inactivation. The MLC kinase inhibitor, ML-7, inhibited ACh-induced MLC phosphorylation by ϳ80% and depressed active force by ϳ70% but did not affect ACh-induced actin polymerization, demonstrating that AChstimulated actin polymerization occurs independently of MLC phosphorylation. We conclude that the RhoA-mediated regulation of ACh-induced contractile tension in ASM results from its role in mediating actin polymerization rather than from effects on MLC phosphatase or MLC phosphorylation. cytoskeleton; calcium sensitization; myosin light chain phosphorylation; myosin light chain phosphatase; myosin phosphatase; calyculin A; myosin light chain kinase

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Muscle Contraction

Squire¹

2011

Encyclopedia of Life Sciences

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Muscular contraction is one of the few biological processes that can be appreciated directly in our everyday lives. In the past few decades a detailed understanding of the underlying molecular processes that produce force and movement has been obtained. Striated muscles contain well organised repeating units called sarcomeres which each include overlapping arrays of filaments of the proteins myosin and actin. Myosin filaments have projections on their surfaces known as crossbridges. These are the myosin head parts of the myosin molecules which form the myosin filament. It is the myosin heads, which are enzymes (ATPases) which interact with actin filaments to produce force and movement. Actin filaments contain additional proteins troponin and tropomyosin which are involved in switching muscle activity on and off (muscle regulation). Key Concepts: Vertebrates have two types of striated muscle namely cardiac muscle, which drives our heart and skeletal muscles which move our skeleton. Vertebrate skeletal muscles contain long thin fibres (multinucleate cells) about 20–100 μm in diameter and very long (mms to cms). Muscle fibres are parallel arrays of long, thin myofibrils about 2–5 μm in diameter and sometimes as long as the fibres. Cardiac muscle cells (myocytes) are much shorter than skeletal muscle fibres and link end‐to‐end to provide long lengths of muscle. They also contain myofibrils. The basic repeating unit in all striated muscles is the sarcomere. In vertebrates this is about 2–2.5 μm long. A myofibril is a long string of sarcomeres. The sarcomere comprises overlapping arrays of myosin and actin filaments. Myosin filaments are made of myosin molecules which consist of a rod‐shaped region with two heads on. The myosin heads projecting from the myosin filament surface can hydrolyse ATP (adenosine triphosphate; they are ATPase enzymes), a process which is accelerated when heads interact with actin to produce force and movement. In striated muscles the interaction of myosin heads with actin is controlled by the proteins troponin and tropomyosin on the actin filaments. It is calcium ions released by the sarcoplasmic reticulum around myofibrils in response to nervous stimulus that interact with troponin, move tropomyosin and allow the actin–myosin interaction to proceed.

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Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction

Abstract: Gunst SJ, Zhang W. Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction.

Cited by 323 publications

References 151 publications

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

The effects of the small GTPase RhoA on the muscarinic contraction of airway smooth muscle result from its role in regulating actin polymerization

Muscle Contraction

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