doi: 10.1161/01.RES.0000233147.38981.90
© 2006 American Heart Association, Inc.
Editorials |
Molecular Coding of Kv1 Channels to Oppose Myogenic Constriction
From the University of Vermont, Department of Pharmacology, Burlington, Vt.
Correspondence to Mark T. Nelson, Department of Pharmacology, University of Vermont, Given Building, Room B-333, 89 Beaumont Avenue, Burlington VT 05405-0068. E-mail Mark.Nelson{at}uvm.edu
See related article, pages 53–60
Key Words: voltage-gated potassium channel • myogenic response • vascular smooth muscle • cerebral circulation • Kv1 channel
Resistance arteries possess an intrinsic ability to constrict in response to increased intraluminal pressure, the "myogenic response."1 The ability of resistance vessels to modulate their diameter in response to changes in intraluminal pressure is thought to be an important component of blood flow autoregulation, such that constant blood flow and tissue perfusion are maintained in the face of variations in blood pressure.2,3 Specifically, intraluminal pressure results in a graded smooth muscle cell (SMC) depolarization from about –65 mV to about –40 mV,4 likely because of activation of nonselective cation channels.5 This depolarization activates L-type voltage-dependent calcium (Ca2+) channels, leading to elevation of the SMC cytosolic Ca2+ concentration, SMC contraction, and vasoconstriction.6 In the absence of negative feedback mechanisms to oppose myogenic constriction, resistance arteries would likely exhibit unstable membrane potentials and fluctuations in vascular diameter as a result of Ca2+ dependent action potentials.7 However, in vivo, graded and sustained changes in vascular diameter occur, such that blood flow is maintained despite changes in pressure.1 Activation of hyperpolarizing potassium (K+) conductances, which oppose depolarization and vasoconstriction, are critical negative feedback mechanisms responsible for controlling the extent of myogenic constriction.2,3,8–10
Smooth muscle cells express two types of K+ channels which are primarily responsible for opposing myogenic depolarization: (1) the large conductance Ca2+ sensitive K+ (BK) channel, which is activated by both membrane depolarization and intracellular Ca2+,8,11 and (2) voltage-gated K+ channels (KV channels), which are steeply activated by membrane potential (Vm) depolarization.9,10,12,13 Interestingly, BK channels appear to be under the control of spatially-localized micromolar increases in Ca2+ mediated by transient Ca2+ release events from ryanodine receptors (Ca2+ sparks).3,11,14 Through BK channels, Ca2+ sparks regulate Vm, vascular tone, and blood pressure.11,15 KV channels act in concert with BK channels to regulate SMC Vm and vascular diameter and thus also play a significant role in regulating vascular tone. Inhibition of KV channels, for example with the classical inhibitors tetraethylammonium ions (TEA, 
1 mmol/L) or 4-aminopyridine (4-AP), leads to a dramatic SMC depolarization (&20 mV) and vasoconstriction (&30%).4,9,10,13 Furthermore, KV channel inhibition leads to increased myogenic tone at a given pressure,4,9,10 suggesting that under physiological conditions, KV channels serve to oppose myogenic constriction. The challenge, addressed by Chen et al16 in this issue of Circulation Research, is to identify the molecular nature of the KV channel that has the unique properties to modulate the myogenic response.
The KV channel family comprises 12 subfamilies of related genes (KV1 to 12) that form the 
pore-forming subunits.17,18 Although the expression of different KVß subunits can serve to modulate channel activity,18,19 KV subunits with distinct biophysical characteristics can assemble as heterotetramers, enabling the formation of a diverse array of functional channels that operate within the physiologically relevant conditions of a particular cellular system.9,10,20 Furthermore, the expression profile of KV channels may be tuned to satisfy the needs of a given system. For example, Plane et al9 have shown that the relative expression of message for KV1 subunits is significantly greater in 1st and 2nd order rat mesenteric arteries compared with 4th order arteries.
Biophysical measurements and pharmacological inhibitors with varying specificities have traditionally been used to probe KV channel function in vascular SMCs.3,7,20,21 TEA and 4-AP are relatively nonselective inhibitors of KV channels, with TEA also inhibiting BK channels.3 Correolide is often used to probe the contribution of KV1 channels to the generation of functional KV current, although it can also bind to KV2 subunits, albeit with much lower affinity than KV1 subunits.21 Given that heterotetrameric channels are expressed in vascular SMCs, and KV channels exhibit significant similarities in their activation and inactivation characteristics, conductance, and pharmacological sensitivities, it is difficult to conclusively gauge the relative contributions of each subtype to the functional KV current using traditional methods.
To overcome these issues, Chen et al16 used a dominant-negative cDNA construct to suppress KV1 currents in rat middle cerebral artery, and provide elegant molecular evidence for the involvement of KV1 containing channels in the regulation of vascular function. Specifically, a mutant KV1.5 construct (KV1.5DN) containing a single tryptophan to phenylalanine substitution in the pore-forming region was transfected into reverse permeabilized cerebral arteries, under the assumption that the mutant subunits would coassemble with endogenous KV1 subunits to form nonfunctional KV1 channels independent of subunit composition or stoichiometry. This dominant negative construct has previously been shown to prevent K+ permeation through the channel without altering channel expression.22 Importantly, Chen et al16 verified that this construct specifically suppressed KV1 but not KV2 currents in a heterologous expression system, and that it did not affect the levels of other known components of the myogenic response. Myogenic constriction was enhanced in cerebral arteries overexpressing KV1.5DN and decreased in arteries overexpressing wild-type KV1.5 without affecting passive response characteristics in the absence of extracellular Ca2+ over a range of intraluminal pressures. This effect of the dominant-negative channel on myogenic tone appears attributable to an exaggerated depolarization of the SMC Vm evoked by intraluminal pressure, as would be expected in the presence of crippled KV channel function. Specifically, SMCs in KV1.5DN transfected arteries were more depolarized than SMCs in mock transfected arteries pressurized to 80 mm Hg, whereas SMCs in arteries transfected with wild-type KV1.5 were more hyperpolarized at identical pressure. In addition, correolide treatment had divergent effects on myogenic constriction of arteries transfected with KV1.5DN versus arteries overexpressing wild-type KV1.5, consistent with the assertion that KV1.5DN serves to suppress the function of KV1 containing channels that are involved in the myogenic response. These findings provide important insights into the composition of the molecular machinery responsible for modulating the level of myogenic depolarization in the vasculature and demonstrate the utility of a molecular-based approach to manipulate cellular components that underlie normal vascular function.
The molecular coding of KV channels is central to the proper function of different types of smooth muscle. For example, urinary bladder smooth muscle exhibits rapid action potentials and prolonged afterhyperpolarizations, and KV2 family members, based on their kinetic properties, are key to this function.23 However, in vascular smooth muscle, which do not typically fire action potentials and depend on graded changes in Vm, KV1 channels have a dominant role in opposing excitability.9,10,13,16 Thus, disabling KV1 channel function would render vascular smooth muscle virtually defenseless to the depolarizing and vasoconstricting forces of intraluminal pressure and vasoconstricting agonists. Based on the current study and previous investigations of the role of KV channels in the vasculature, it is clear that KV1 channels underlie the regulation of vascular smooth muscle Vm over a wide range of physiologically relevant potentials (–65 to –40 mV) and constitute a critical negative feedback mechanism for regulating the extent of myogenic constriction. This body of work provides strong impetus to explore the involvement of endogenous modulators of KV1 channel activity in the regulation of vascular function as well as the potential role of KV1 channel dysfunction in pathological conditions such as hypertension and vasospasm.24
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Acknowledgments |
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Sources of Funding
This work was supported by the National Heart, Lung, and Blood Institute (HL44455) and the Totman Trust for Medical Research.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
- Key Role of Kv1 Channels in Vasoregulation
- Tim T. Chen, Kevin D. Luykenaar, Emma J. Walsh, Michael P. Walsh, and William C. Cole
Circ. Res. 2006 99: 53-60.[Abstract] [Full Text] [PDF]
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