Kv2 channels oppose myogenic constriction of rat cerebral arteries
ABSTRACT By hyperpolarizing arterial smooth muscle, voltage-gated, Ca2+-independent K+ (Kv) channels decrease calcium influx and thus oppose constriction. However, the molecular nature of the Kv channels function in arterial smooth muscle remains controversial. Recent investigations have emphasized a predominant role of Kv1 channels in regulating arterial tone. In this study, we tested the hypothesis Kv2 channels may also significantly regulate tone of rat cerebral arteries. We found that Kv2.1 transcript and protein are present in cerebral arterial smooth muscle. In addition, our analysis indicates that a substantial component (approximately 50%) of the voltage dependencies and kinetics of Kv currents in voltage-clamped cerebral arterial myocytes is consistent with Kv2 channels. Accordingly, we found that stromatoxin, a specific inhibitor of Kv2 channels, significantly decreased Kv currents in these cells. Furthermore, stromatoxin enhanced myogenic constriction of pressurized arterial segments. We also found that during angiotensin II-induced hypertension, Kv2 channel function was reduced in isolated myocytes and in intact arteries. This suggests that impaired Kv2 channel activity may contribute to arterial dysfunction during hypertension. On the basis of these novel observations, we propose a new model of Kv channel function in arterial smooth muscle in which Kv2 channels (in combination with Kv1 channels) contribute to membrane hyperpolarization and thus oppose constriction.
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- "subunits could be identified   . In situ hybridization revealed the presence of different BK channel splice variants (X1 +24 , X2 +92 , SS2 +174 and SS4 +81 ) in combination with β1, β2, and β4 subunits in rat cerebral arteries . "
ABSTRACT: Healthy cerebrovascular myocytes express members of several different ion channel families which regulate resting membrane potential, vascular diameter, and vascular tone and are involved in cerebral autoregulation. In animal models, in response to subarachnoid blood, a dynamic transition of ion channel expression and function is initiated, with acute and long-term effects differing from each other. Initial hypoperfusion after exposure of cerebral vessels to oxyhemoglobin correlates with a suppression of voltage-gated potassium channel activity, whereas delayed cerebral vasospasm involves changes in other potassium channel and voltage-gated calcium channels expression and function. Furthermore, expression patterns and function of ion channels appear to differ between main and small peripheral vessels, which may be key in understanding mechanisms behind subarachnoid hemorrhage-induced vasospasm. Here, changes in calcium and potassium channel expression and function in animal models of subarachnoid hemorrhage and transient global ischemia are systematically reviewed and their clinical significance discussed.12/2012; 2012:382146. DOI:10.1155/2012/382146
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- "Within hippocampal neurons Kv2.1 regulates the action potential waveform, especially during high-frequency stimulation (Du et al., 2000). In pulmonary vascular smooth muscle Kv2.1 represents a hypoxia-sensitive channel that regulates the membrane potential and thus smooth muscle contraction (Patel et al., 1997; Hulme et al., 1999), and in cerebral artery smooth muscle Kv2.1 regulates myogenic constriction (Amberg and Santana, 2006). In the myocardium Kv2.1 generates the "
ABSTRACT: Voltage-gated K(+) (Kv) channels regulate membrane potential in many cell types. Although the channel surface density and location must be well controlled, little is known about Kv channel delivery and retrieval on the cell surface. The Kv2.1 channel localizes to micron-sized clusters in neurons and transfected human embryonic kidney (HEK) cells, where it is nonconducting. Because Kv2.1 is postulated to be involved in soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated membrane fusion, we examined the hypothesis that these surface clusters are specialized platforms involved in membrane protein trafficking. Total internal reflection-based fluorescence recovery after photobleaching studies and quantum dot imaging of single Kv2.1 channels revealed that Kv2.1-containing vesicles deliver cargo at the Kv2.1 surface clusters in both transfected HEK cells and hippocampal neurons. More than 85% of cytoplasmic and recycling Kv2.1 channels was delivered to the cell surface at the cluster perimeter in both cell types. At least 85% of recycling Kv1.4, which, unlike Kv2.1, has a homogeneous surface distribution, is also delivered here. Actin depolymerization resulted in Kv2.1 exocytosis at cluster-free surface membrane. These results indicate that one nonconducting function of Kv2.1 is to form microdomains involved in membrane protein trafficking. This study is the first to identify stable cell surface platforms involved in ion channel trafficking.Molecular biology of the cell 05/2012; 23(15):2917-29. DOI:10.1091/mbc.E12-01-0047 · 5.98 Impact Factor
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- "RMCA myocytes were previously shown to express Kv1 (Albarwani et al. 2003; Chen et al. 2006) and Kv2-containing (Amberg & Santana, 2006; Zhong et al. 2010 "
ABSTRACT: KCNQ gene expression was previously shown in various rodent blood vessels, where the products of KCNQ4 and KCNQ5, Kv7.4 and Kv7.5 potassium channel subunits, respectively, have an influence on vascular reactivity. The aim of this study was to determine if small cerebral resistance arteries of the rat express KCNQ genes and whether Kv7 channels participate in the regulation of myogenic control of diameter. Quantitative reverse transcription polymerase chain reaction (QPCR) was undertaken using RNA isolated from rat middle cerebral arteries (RMCAs) and immunocytochemistry was performed using Kv7 subunit-specific antibodies and freshly isolated RMCA myocytes. KCNQ4 message was more abundant than KCNQ5 = KCNQ1, but KCNQ2 and KCNQ3 message levels were negligible. Kv7.1, Kv7.4 and Kv7.5 immunoreactivity was present at the sarcolemma of freshly isolated RMCA myocytes. Linopirdine (1 microm) partially depressed, whereas the Kv7 activator S-1 (3 and/or 20 microm) enhanced whole-cell Kv7.4 (in HEK 293 cells), as well as native RMCA myocyte Kv current amplitude. The effects of S-1 were voltage-dependent, with progressive loss of stimulation at potentials of >15 mV. At the concentrations employed linopirdine and S-1 did not alter currents due to recombinant Kv1.2/Kv1.5 or Kv2.1/Kv9.3 channels (in HEK 293 cells) that are also expressed by RMCA myocytes. In contrast, another widely used Kv7 blocker, XE991 (10 microm), significantly attenuated native Kv current and also reduced Kv1.2/Kv1.5 and Kv2.1/Kv9.3 currents. Pressurized arterial myography was performed using RMCAs exposed to intravascular pressures of 10-100 mmHg. Linopirdine (1 microm) enhanced the myogenic response at 20 mmHg, whereas the activation of Kv7 channels with S-1 (20 microm) inhibited myogenic constriction at >20 mmHg and reversed the increased myogenic response produced by suppression of Kv2-containing channels with 30 nm stromatoxin (ScTx1). These data reveal a novel contribution of KCNQ gene products to the regulation of myogenic control of cerebral arterial diameter and suggest that Kv7 channel activating drugs may be appropriate candidates for the development of an effective therapy to ameliorate cerebral vasospasm.The Journal of Physiology 09/2010; 588(Pt 17):3277-93. DOI:10.1113/jphysiol.2010.192823 · 4.54 Impact Factor