A spoonful of sugar helps the KV channel activity go down.

Abstract

Modulation of vascular smooth muscle cell (SMC) potassium (K+) channel function has a profound influence on SMC contractility and vascular function. Depolarization of SMCs activates L-type voltage-dependent Ca2+ channels resulting in Ca2+ influx, elevation of SMC cytosolic Ca2+, and contraction. The membrane potential (Vm) of vascular SMCs is tightly controlled by a complement of K+ channels expressed by vascular SMCs, whose activity serves to counteract depolarizing influences induced by constricting stimuli including intravascular pressure and vasoactive substances. Vascular smooth muscle can express large conductance, voltage- and calcium-sensitive K+ (BK) channels, strong inward rectifier K+ (Kir) channels, ATP-sensitive (KATP) K+ channels, and voltage dependent K+ (KV) channels, which are activated and modulated through different mechanisms to allow for the fine tuning of SMC Vm throughout the physiological range (−60 to −40 mV) (Nelson & Quayle, 1995). The activity of voltage-dependent potassium (KV) channels is an important determinant of the SMC Vm, and vascular tone (Knot & Nelson, 1995; Cox & Rusch, 2002; Cole et al. 2005; Plane et al. 2005). Modulation of KV channel activity can occur is through alteration of KV channel expression levels. Cole and colleagues (Chen et al. 2006) utilized overexpression of wild-type and dominant negative KV1.5 subunits in middle cerebral arteries to demonstrate that decreasing the expression of KV1 subunits in this system causes arteries to be more depolarized and constricted in response to intravascular pressure Increasing KV channel expression results in the opposite effect. Reduced arterial KV channel expression likely contributes to certain pathological conditions such as cerebral vasospasm (Ishiguro et al. 2006). KV channel activity can also be regulated through the action of various kinases such as protein kinase C (PKC), which can be activated in response to vasoactive substances such as angiotensin II (Clement-Chomienne et al. 1996) and endothelin-1 (ET-1) (Shimoda et al. 1998). Activation of PKC serves to reduce KV channel currents, leading to a more depolarized SMC Vm, and increased vascular tone. In this issue of The Journal of Physiology, Rainbow et al. (2006) provide evidence for a mechanism through which KV channel activity in mesenteric artery SMCs is rapidly modulated by variations in glucose concentration within the normal physiological range, a process which is dependent on PKC activity. Specifically, increasing glucose concentration between 0 and 10 mm results in a decrease of whole cell KV channel current and depolarization of SMCs within intact mesenteric arteries. This effect requires PKC activity, as preincubation with a PKC inhibitory peptide blocks the effect of glucose elevation. Glucose metabolism is necessary to induce this effect, since non-metabolizable mono- or disaccharides were incapable of producing this response. Interestingly, the effects of glucose on KV currents were rapid and reversible, with the complete effect occurring within 200 s of glucose application. Perhaps most significantly, Rainbow et al. show that elevated glucose can interfere with endo-genous signalling pathways utilized for communication between the endothelium and SMCs. Exposure of SMCs to ET-1 is known to increase the rate of KV channel inactivation and reduce whole cell KV channel currents in vascular SMCs in a PKC-dependent manner. The current study illustrates that elevated glucose prevents this ET-1 induced suppression of KV channel currents, but interestingly is without effect on ET-1 induced suppression of KATP channel current. These findings suggest that physiological levels of glucose have a significant impact on the ability of vascular KV channels to regulate SMC contractility and vascular tone, which is likely to increase vascular resistance and decrease tissue perfusion. The study of Rainbow et al. raises several significant and interesting points. First, these findings imply that vascular SMCs possess an intrinsic ability to act as metabolic sensors, and alter their contractile state to modulate tissue perfusion based on local metabolic requirements. Such a mechanism would be of obvious and profound importance in the brain, where a constant glucose supply is essential. These findings suggest that, under hypoglycaemic conditions, KV channel activity would increase, hyperpolarizing SMCs and dilating cerebral vessels, thus increasing the delivery of energetic substrates. Such a mechanism could be involved in the hyperaemic response, whereby neuronal activity (and presumably increased neuronal metabolic demand) is translated into spatially localized increases in cerebral blood flow. Furthermore, these findings imply that abnormally elevated glucose levels associated with diabetes would directly and persistently alter the excitability of vascular SMCs, leading to increased vascular resistance and, potentially, hypertension. In future studies, it will be of fundamental importance to discern how glucose levels are decoded by SMCs, what signalling cascades are affected by elevated glucose, and how SMC KV and other ion channel activity is affected by endogenous factors to induce changes in vascular tone and blood flow. The current study adds to an emerging body of evidence expounding the significance of dynamic regulation of KV channel activity in the physiological control of vascular function (Knot & Nelson, 1995; Cox & Rusch, 2002; Cole et al. 2005; Plane et al. 2005), and provides an elegant example of the processes linking cellular metabolic state to blood flow.