Cation channels of the transient receptor potential superfamily: Their role in physiological and pathophysiological processes of smooth muscle cells

Dietrich, Alexander; Chubanov, Vladimir; Kalwa, Hermann; Rost, Benjamin R.; Gudermann, Thomas

doi:10.1016/j.pharmthera.2006.05.013

Cited by 165 publications

(118 citation statements)

References 169 publications

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“…Several members of the canonical transient receptor potential channel (TRPC) family act as Ca 2ϩ -permeable cation channels that can be activated in response to stimulation of G protein (G q/11 )-coupled receptors (8,12). TRPC6 is highly expressed in vascular smooth muscle cells and has been suggested to be the molecular correlate of the ␣ 1 -adrenoceptoractivated nonselective cation channel in rabbit portal vein (1,12) and mesenteric artery (11) myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, TRPC6 and one of its splicing variant (TRPC6␣) are expressed in corporal myocytes from human CC (27), and, therefore, this TRPC subtype could be a molecular candidate for the nonselective cation channel activated by ␣ 1 -adrenoceptors and regulated by Rho kinase in penile arteries. However, TRPC proteins can form heteromeric and homomeric channels (8), and, therefore, specific molecular and functional studies are needed to clarify the expression of the various TRPC subunits, its possible contribution to ROC entry, and its specific regulation by Rho kinase in penile arteries.…”

Section: Discussionmentioning

confidence: 99%

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Rho kinase is involved in Ca²⁺ entry of rat penile small arteries

Villalba¹,

Stankevičius²,

Simonsen³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Tonic physiological activity of RhoA/Rho kinase contributes to the maintenance of penile flaccidity through its involvement in the Ca 2ϩ sensitization of erectile tissue smooth muscle. The present study hypothesized that Rho kinase is also involved in the modulation of Ca 2ϩ entry induced by ␣1-adrenoceptor stimulation of penile arteries. Rat penile arteries were mounted in microvascular myographs for simultaneous measurements of intracellular Ca 2ϩ ([Ca 2ϩ ]i) and force. The Rho-kinase inhibitor Y-27632 markedly reduced norepinephrine-mediated electrically induced contractions and the increases in both [Ca 2ϩ ]i and tension elicited by the ␣1-adrenoceptor agonist phenylephrine (Phe). In contrast, the protein kinase C (PKC) inhibitor Ro-31-8220 reduced tension without altering the Phe-induced increase in [Ca 2ϩ ]i. In the presence of nifedipine, Y-27632 still inhibited the non-L-type Ca 2ϩ signal and blunted Phe contraction. Y-27632 did not impair the capacitative Ca 2ϩ entry evoked by store depletion with cyclopiazonic acid but largely reduced the Ba 2ϩ influx stimulated by Phe in fura-2 AM-loaded arteries. The addition of Y-27632 to arteries depolarized with high KCl markedly reduced tension without changing [Ca 2ϩ ]i. In ␣-toxin-permeabilized penile arteries stimulated with threshold Ca 2ϩ concentrations, Y-27632 inhibited the sensitization induced by either guanosine 5Ј-O-(3-thiotriphosphate) (GTP␥S) or Phe in the presence of GTP␥S. However, Y-27632 failed to alter contractions induced by a maximal concentration of free Ca 2ϩ . These results suggest that Rho kinase, besides its contribution to the Ca 2ϩ sensitization of the contractile proteins, is also involved in the regulation of Ca 2ϩ entry through a nonselective cation channel activated by ␣1-adenoceptor stimulation in rat penile arteries. penile arteries; calcium entry; nonselective cation channels; calcium sensitization PENILE ERECTION OCCURS when nitric oxide (NO) released from nerves and endothelium upon sexual stimulation relaxes smooth muscle of the corpus cavernosum (CC) and penile arteries, leading to blood filling of the sinuses and restriction of venous outflow (2, 25). During the flaccid state, erectile tissue is contracted by the release of neural and local factors, such as norepinephrine, neuropeptide Y, endothelin-1, and prostanoids that increase smooth muscle cytosolic Ca 2ϩ ([Ca 2ϩ ] i ) and/or Ca 2ϩ sensitization through activation G protein-coupled receptors (2,20,25). Erectile dysfunction (ED), considered as a sign of early endothelial dysfunction and cardiovascular disease, is three times more prevalent in men with Types 1 and 2 diabetes than in men without diabetes (3, 33). About 50% of these patients exhibit suboptimal responses to oral phophodiestarase 5 inhibitors, such as sildenafil (33), that enhance the NOmediated vasodilatation leading to penile erection. As an alternative, inhibition of the Rho/Rho-kinase signaling pathway has been proposed as a potential molecular target for the development of novel therapies for ED si...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rho kinase is involved in Ca²⁺ entry of rat penile small arteries

Villalba¹,

Stankevičius²,

Simonsen³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Among the TRPC channels, TRPC3, -6, and -7 are 75% identical and gated by pathways that activate C-type phospholipases (PLCs) as well as by direct exposure to diacylglycerols (DAGs) (10). Although TRPC6 is expressed in many smooth-muscle tissues (11) and is thought to be an essential regulator of smooth-muscle contractility (12)(13)(14), direct evidence for a unique, nonredundant physiological role in the pulmonary circulation is still lacking. However, recently an up-regulation of TRPC6 has been shown in lung tissue from patients suffering from chronic pulmonary hypertension (15).…”

mentioning

confidence: 99%

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Weißmann

Dietrich

Fuchs

et al. 2006

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

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Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6 ؊/؊ mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6 ؊/؊ but not in WT mice. This effect was mirrored by a lack of hypoxiainduced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6 ؊/؊ mice. In both WT and TRPC6 ؊/؊ PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6 ؊/؊ PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.hypoxia-induced diacylglycerol accumulation ͉ precapillary pulmonary arterial smooth-muscle cells ͉ pulmonary hypertension ͉ transient receptor potential channel 6-deficient mouse model ͉ arterial hypoxemia A cute regional hypoxic pulmonary vasoconstriction (HPV) is necessary to maintain optimized gas exchange by directing blood flow from poorly ventilated to well ventilated areas of the lung. Under conditions of generalized hypoxia, however, total pulmonary vascular resistance rises with subsequent increase of right heart load (1-3). Chronic hypoxia, as occurring in ventilatory disorders induces chronic pulmonary hypertension, pulmonary vascular remodeling, and cor pulmonale (4). The underlying oxygen sensing and signal transduction mechanisms of the acute and chronic vascular responses are largely unknown. A rise of intracellular calcium ([Ca 2ϩ ] i ) in pulmonary artery smooth-muscle cells (SMCs) has been suggested to be the key event in these processes (5-8). However, the question how [Ca 2ϩ ] i is regulated has not yet been resolved. Among others, transient receptor potential (TRP) channels are regulators of [Ca 2ϩ ] i . The TRP protein superfamily consists of a diverse group of nonselective cation channels involved in many basic cellular processes (9). Whereas members of the TRPV and TRPM subfamilies have emerged as versatile cellular sensors, the functional importance of the seven members (TRPC1 to -7) of the TRPC (transient receptor potential cation channel subfamily C) subfamily...

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“…These indicate that the response is mediated by the voltage-independent, receptor-operated and store-operated calcium entry (Elliott, 2001;McFadzean and Gibson, 2002;Wray et al, 2005;Thorneloe and Nelson, 2005). The store-operated calcium entry might be a subtype of transient receptor potential families (Pedersen et al, 2005;Dietrich et al, 2006). Exogenously applied noradrenaline and adrenaline produced a contraction of the guinea-pig muscularis mucosae with resting tone via α1-adrenoceptors, but inhibited the sustained contraction induced by carbachol or high potassium via β1-adrenoceptors Uchida, 1983;Uchida et al, 1983;Kamikawa and Shimo, 1987;Horinouchi et al, 2003).…”

Section: Responsiveness To Drugsmentioning

confidence: 95%

Muscularis mucosae - the forgotten sibling

Uchida

Kamikawa

2007

J. Smooth Muscle Res.

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Lamina muscularis mucosae sitting beneath mucosal surface of the digestive tract has received little attention to date compared with external smooth muscle layers. Motor activity of the muscularis mucosae shows a great regional and species difference. Autonomic innervation profile is also different from esophagus to colon or between animal species. Intracellular transduction mechanisms for motor activity of the muscularis mucosae are also different from those of external longitudinal and circular muscles or from vascular and airway smooth muscles. Since the submucosal area is a major source for eicosanoid production, abnormality of muscularis mucosae motor activity may link with abnormality of mucosal absorption and secretion functions. Inflammatory bowel diseases such as diarrhea, irritable bowel syndrome and Crohn's disease accompanied with altered motor activity of the muscularis mucosae. Much attention should be attracted to the human muscularis mucosae as a new therapeutic target for inflammatory bowel diseases.

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Cation channels of the transient receptor potential superfamily: Their role in physiological and pathophysiological processes of smooth muscle cells

Cited by 165 publications

References 169 publications

Rho kinase is involved in Ca²⁺ entry of rat penile small arteries

Rho kinase is involved in Ca²⁺ entry of rat penile small arteries

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Muscularis mucosae - the forgotten sibling

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Cation channels of the transient receptor potential superfamily: Their role in physiological and pathophysiological processes of smooth muscle cells

Cited by 165 publications

References 169 publications

Rho kinase is involved in Ca2+ entry of rat penile small arteries

Rho kinase is involved in Ca2+ entry of rat penile small arteries

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Muscularis mucosae - the forgotten sibling

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Rho kinase is involved in Ca²⁺ entry of rat penile small arteries

Rho kinase is involved in Ca²⁺ entry of rat penile small arteries