Smoothelin contains a novel actin cytoskeleton localization sequence with similarity to troponin T

Quensel, Christina; Krämer, Jochen; Cardoso, M. Cristina; Leonhardt, Heinrich

doi:10.1002/jcb.10143

Cited by 16 publications

(18 citation statements)

References 27 publications

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“…Instead, smooth muscle tropomyosin interacts with h-caldesmon and SM-calponin, which partly take over the role of troponins. 5 Importantly, smoothelins contain a 37-amino acid sequence that is similar to the tail domain of troponin T. 10 In skeletal muscle, this domain not only is required for troponin T interaction with tropomyosin but also is involved in the activation of actomyosin ATPase. 27 Thus, smoothelins might be part of a smooth muscle tropomyosintroponin-like system.…”

Section: Discussionmentioning

confidence: 99%

“…6 -9 They are encoded by a single-copy gene that generates 2 major isoforms, both containing a troponin T-like domain. 10 The smaller smoothelin-A isoform is expressed most prominently in visceral SMCs. In contrast, the 110-kDa smoothelin-B, which is encoded by the smoothelin-A exons plus 10 upstream exons, is found only in vascular SMCs.…”

Section: Clinical Perspective P 836mentioning

confidence: 99%

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Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

et al. 2008

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Background-Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B Ϫ/Ϫ mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B Ϫ/Ϫ ). Methods and Results-Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B Ϫ/Ϫ mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B Ϫ/Ϫ compound mutant mice exhibited a similar contractile deficit. Smtn-B Ϫ/Ϫ arteries had a normal architecture and expressed normal levels of other smooth muscle cell-specific genes, including smooth muscle myosin heavy chain, ␣-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B Ϫ/Ϫ arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B Ϫ/Ϫ mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B Ϫ/Ϫ mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. Key Words: hypertension Ⅲ hypertrophy Ⅲ muscle contraction Ⅲ muscle, smooth Ⅲ vascular resistance H ypertension is a common condition in Western countries, affecting Ϸ27% of the population worldwide. It is a major risk factor for the development of life-threatening conditions such as coronary heart disease and stroke. However, the cause of increased blood pressure is unknown in most patients. 1 Smooth muscle contractility is one of the primary determinants of vascular resistance, thereby contributing significantly to the maintenance of a physiological blood pressure. Accordingly, molecular defects in the regulation or mechanics of arterial smooth muscle contraction generally cause profound cardiovascular phenotypes. For example, ␣-smooth muscle actin (␣-SMA) knockout mice display impaired vascular contractility and reduced blood flow. 2 Likewise, smooth muscle myosin heavy chain (SM-MHC)-B knockouts show a significant decrease in maximal shortening velocity of vascular smooth muscle, 3 and SM-calponin-deficient mice have impaired mean arterial pressure (MAP) regulation. 4 Clinical Perspective p 836Despite the importance of smooth muscle cell (SMC) contraction for the cardiovascular system, the contractile process itself is still incompletely understood. In particular, the functions of regulatory proteins that are connected to the actin-myosin filaments in vascular SMCs remain poorly defined. 5 Candidate thin filament regulatory proteins that have not been studied in th...

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective P 836mentioning

confidence: 99%

Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

et al. 2008

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“…Two isoforms of smoothelin have been identified: a 59 kDa isoform (smoothelin A) that is expressed in visceral smooth muscle such as intestine [33] and a 100 kDa isoform (smoothelin B) that is expressed in vascular smooth muscle [34]. More recently, Leonhart and colleagues [36] have defined two alternate splice variants that contain spectrin family similarity. In this report, we present an additional member of the smoothelin family of proteins.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that two CH-domains in tandem are required for actinbinding (reviewed in [41]). The smoothelins possess novel actin binding domains that are responsible for association with actin containing filaments [36]. The large vascular specific smoothelin isoform contains two actin binding domains, whereas the small visceral specific isoform contains only one actin binding domain (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins

2004

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Cyclic nucleotides acting through their associated protein kinases, the cGMP-and cAMP-dependent protein kinases, can relax smooth muscles without a change in free intracellular calcium concentration ([Ca 2þ ] i ), a phenomenon referred to as Ca 2þ desensitization. The molecular mechanisms by which these kinases bring about Ca 2þ desensitization are unknown and an understanding of this phenomenon may lead to better therapies for treating diseases involving defects in the contractile response of smooth muscles such as hypertension, bronchospasm, sexual dysfunction, gastrointestinal disorders and glaucoma. Utilizing a combination of real-time proteomics and smooth muscle physiology, we characterized a distinct subset of protein targets for cGMP-dependent protein kinase in smooth muscle. Among those phosphoproteins identified was calponin homology-associated smooth muscle (CHASM), a novel protein that contains a calponin homology domain and shares sequence similarity with the smoothelin family of smooth muscle specific proteins. Recombinant CHASM was found to evoke relaxation in a concentration dependent manner when added to permeabilized smooth muscle. A co-sedimentation assay with actin demonstrated that CHASM does not possess actin binding activity. Our findings indicate that CHASM is a novel member of the smoothelin protein family that elicits Ca 2þ desensitization in smooth muscle.

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In situ Analysis of Smoothelin‐like 1 and Calmodulin Interactions in Smooth Muscle Cells by Proximity Ligation

Ulke‐Lemée¹,

Turner²,

MacDonald³

2015

J of Cellular Biochemistry

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The smoothelin-like 1 (SMTNL1) protein is the newest member of the smoothelin family of muscle proteins. Two calmodulin (CaM)-binding domains (CBD1 for Ca-CaM; CBD2 for apo-CaM) have been described for the SMTNL1 protein using in vitro assays. We now demonstrate in situ associations of SMTNL1 and CaM in A7r5 smooth muscle cells using the proximity ligation assay (PLA). We quantified CaM-SMTNL1 proximity events accurately after taking into account variations in protein expression levels. The refined method allows quantification of in situ proximity after transient transfection with an associated error of <10%. The proximity of SMTNL1 and CaM in A7r5 cells could be reduced by scrambling the amino acid sequence and mutation of large hydrophobic amino acids of CBD1. The truncation of CBD2 did not influence SMTNL1 proximity to CaM. Ultimately, we conclude that SMTNL1 forms complex interactions with CaM in smooth muscle cells, with a role for CBD1 and possibly the intrinsically disordered region.

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Smoothelin contains a novel actin cytoskeleton localization sequence with similarity to troponin T

Cited by 16 publications

References 27 publications

Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins

In situ Analysis of Smoothelin‐like 1 and Calmodulin Interactions in Smooth Muscle Cells by Proximity Ligation

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