Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 ([Ca2+]i), a phenomenon referred to as Ca2+ desensitization. The molecular mechanisms by which these kinases bring about Ca2+ 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 Ca2+ desensitization in smooth muscle.
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PMID:Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins. 1532 99

Relaxation of smooth muscle can occur through agonists (such as nitric oxide) that activate guanylyl cyclase and stimulate the production of cGMP, activating its target, cGMP-dependent protein kinase (PKG). This kinase can raise the Ca2+ threshold for contraction, thus causing Ca2+ desensitization, but the mechanism for this event is not completely understood. Ca2+ sensitization/desensitization pathways are essential for maintenance of normal smooth muscle tone, and abnormalities in these pathways have been shown to be key components in the pathogenesis of diseases such as hypertension and asthma in humans. Our laboratory has devised a proteomic method to specifically address the question of what proteins are early phosphorylation targets in calcium desensitization. Using ileum smooth muscle, we metabolically labeled the muscle with (32P)-orthophosphate, permeabilized the muscle, established constant calcium concentrations, and stimulated with 8-bromo-cGMP, which activates PKG. Proteins whose phosphorylation state changed in response to cGMP at constant levels of calcium were separated with two-dimensional gel electrophoresis, identified by autoradiography, and sequenced with nanospray mass spectrometry. Using this technique, we identified a previously uncharacterized PKG phosphoprotein, which we have termed CHASM (Calponin Homology Smooth Muscle protein). Using physiological muscle bath contraction studies, we have validated CHASM as a component of calcium desensitization pathways in smooth muscle.
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PMID:Real-time in vivo proteomic identification of novel kinase substrates in smooth muscle. 1717 92

Vascular smooth muscle contraction and the myogenic response regulate blood flow in the resistance vascular and contribute to systemic blood pressure. Three pathways are currently known to contribute to the development of the myogenic response: (i) Ca(2+) -dependent phosphorylation of LC20; (ii) Ca(2+) sensitization through inhibition of myosin phosphatase; and (iii) cortical actin polymerization. A number of regulatory smooth muscle proteins are integrated with these pathways to fine tune the response and facilitate adaptations to vascular (patho)physiologies. Of particular interest is the SMTN family of proteins, consisting of SMTN-A, SMTN-B, and the SMTN-like protein, SMTNL1. The SMTN-B and SMTNL1 proteins are both implicated in regulating smooth muscle contractility and contributing to vascular adaptations associated with hypertension, pregnancy, and exercise training. In the case of SMTNL1, the protein plays multiple roles in regulating contraction through functional interactions with contractile regulators as well as transcriptional control of the contractile phenotype and Ca(2+) -sensitizing capacity. For the first time, preliminary results suggest SMTNL1 is involved in the myogenic response of the cerebral resistance vasculature. In this regard, global SMTNL1 deletion is associated with greater myogenic reactivity of cerebral arterioles, although the precise mechanism accounting for this finding remains to be defined.
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PMID:Novel contributions of the smoothelin-like 1 protein in vascular smooth muscle contraction and its potential involvement in myogenic tone. 2426 1

Smooth muscle cells display distinctive expression and organization of contractile filament proteins, which reflect a unique method of contractile regulation. As the focus of this review, the smoothelin and smoothelin-like family members represent a family of poorly understood muscle proteins that appear to act as structural components of the contractile apparatus. The protein family is characterized by the presence a single C-terminal type-2 calponin homology (CH) domain. Often used as the preferred marker of differentiated contractile smooth muscle cells, smoothelin A and B (SMTN-A and SMTN-B) may influence the contractile potential of smooth muscle cells. The more recently identified smoothelin-like proteins (SMTNL1 and SMTNL2) have more diverse functional implications. SMTNL1 is linked to the regulation of smooth muscle contractility and adaptations of both smooth and skeletal muscle to hypertension, pregnancy, and exercise training. The SMTNL1 protein is suggested to play multiple roles in muscle through functional interactions with contractile regulators (e.g., calmodulin, tropomyosin, and myosin phosphatase) as well as transcriptional control of the contractile phenotype and Ca2+-sensitizing capacity. These effects are associated with acute, reversible changes to the contractile state or long-term adaptations mediated by transcriptional changes in expression of contractile proteins. SMTNL2 remains essentially uncharacterized; however, its expression is high in skeletal muscle and could be associated with differentiating myocytes. Finally, emerging opportunities exist to understand the significance of smoothelins as disease-associated markers and in some cases as specific modulators of pathophysiology.
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PMID:Smoothelins and the Control of Muscle Contractility. 2931 Aug 3