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Intravascular pressure enhances the abundance of functional Kv1.5 channels at the surface of arterial smooth muscle cells.

ABSTRACT: Voltage-dependent potassium (K(v)) channels are present in various cell types, including smooth muscle cells (myocytes) of resistance-sized arteries that control systemic blood pressure and regional organ blood flow. Intravascular pressure depolarizes arterial myocytes, stimulating calcium (Ca(2+)) influx through voltage-dependent Ca(2+) (Ca(v)) channels that results in vasoconstriction and also K(+) efflux through K(v) channels that oppose vasoconstriction. We hypothesized that pressure-induced depolarization may not only increase the open probability of plasma membrane-resident K(v) channels but also increase the abundance of these channels at the surface of arterial myocytes to limit vasoconstriction. We found that K(v)1.5 and K(v)2.1 proteins were abundant in the myocytes of resistance-sized mesenteric arteries. K(v)1.5, but not K(v)2.1, continuously recycled between the intracellular compartment and the plasma membrane in contractile arterial myocytes. Using ex vivo preparations of intact arteries, we showed that physiological intravascular pressure through membrane depolarization or membrane depolarization in the absence of pressure inhibited the degradation of internalized K(v)1.5 and increased recycling of K(v)1.5 to the plasma membrane. Accordingly, by stimulating the activity of Ca(v)1.2, membrane depolarization increased whole-cell K(v)1.5 current density in myocytes and K(v)1.5 channel activity in pressurized arteries. In contrast, the total amount and cell surface abundance of K(v)2.1 were independent of intravascular pressure or membrane potential. Thus, our data indicate that intravascular pressure-induced membrane depolarization selectively increased K(v)1.5 surface abundance to increase K(v) currents in arterial myocytes, which would limit vasoconstriction.

SUBMITTER: Kidd MW

PROVIDER: S-EPMC5705045 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Intravascular pressure enhances the abundance of functional Kv1.5 channels at the surface of arterial smooth muscle cells.

Kidd Michael W MW Leo M Dennis MD Bannister John P JP Jaggar Jonathan H JH

Science signaling 20150818 390

Voltage-dependent potassium (K(v)) channels are present in various cell types, including smooth muscle cells (myocytes) of resistance-sized arteries that control systemic blood pressure and regional organ blood flow. Intravascular pressure depolarizes arterial myocytes, stimulating calcium (Ca(2+)) influx through voltage-dependent Ca(2+) (Ca(v)) channels that results in vasoconstriction and also K(+) efflux through K(v) channels that oppose vasoconstriction. We hypothesized that pressure-induced ...[more]

PMID: 26286025

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Project description:RationaleInositol 1,4,5-trisphosphate (IP(3))-induced vasoconstriction can occur independently of intracellular Ca(2+) release and via IP(3) receptor (IP(3)R) and canonical transient receptor potential (TRPC) channel activation, but functional signaling mechanisms mediating this effect are unclear.ObjectivesStudy mechanisms by which IP(3)Rs stimulate TRPC channels in myocytes of resistance-size cerebral arteries.Methods and resultsImmunofluorescence resonance energy transfer (immuno-FRET) microscopy using isoform-selective antibodies indicated that endogenous type 1 IP(3)Rs (IP(3)R1) are in close spatial proximity to TRPC3, but distant from TRPC6 or TRPM4 channels in arterial myocytes. Endothelin-1 (ET-1), a phospholipase C-coupled receptor agonist, elevated immuno-FRET between IP(3)R1 and TRPC3, but not between IP(3)R1 and TRPC6 or TRPM4. TRPC3, but not TRPC6, coimmunoprecipitated with IP(3)R1. TRPC3 and TRPC6 antibodies selectively inhibited recombinant channels, but only the TRPC3 antibody blocked IP(3)-induced nonselective cation current (I(Cat)) in myocytes. TRPC3 knockdown attenuated immuno-FRET between IP(3)R1 and TRPC3, IP(3)-induced I(Cat) activation, and ET-1 and IP(3)-induced vasoconstriction, whereas TRPC6 channel knockdown had no effect. ET-1 did not alter total or plasma membrane-localized TRPC3, as determined using surface biotinylation. RT-PCR demonstrated that C-terminal calmodulin and IP(3)R binding (CIRB) domains are present in myocyte TRPC3 and TRPC6 channels. A peptide corresponding to the IP(3)R N-terminal region that can interact with TRPC channels activated I(Cat). A TRPC3 CIRB domain peptide attenuated IP(3)- and ET-1-induced I(Cat) activation and vasoconstriction.ConclusionsIP(3) stimulates direct coupling between IP(3)R1 and membrane-resident TRPC3 channels in arterial myocytes, leading to I(Cat) activation and vasoconstriction. Close spatial proximity between IP(3)R1 and TRPC3 establishes this isoform-selective functional interaction.

Project description:Arterial smooth muscle (SM) cells respond autonomously to changes in intravascular pressure, adjusting tension to maintain vessel diameter. The values of membrane potential (Vm) and sarcoplasmic Ca(2+) concentration (Ca(in)) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca(2+) as a signal. This works because the two Ca(2+)-signaling pathways are confined to distinct microdomains in which the Ca(2+) concentrations needed to activate key channels are transiently higher than Ca(in). A mathematical model of an isolated arterial SM cell is presented that incorporates the two types of microdomains. The first type consists of junctions between cisternae of the peripheral sarcoplasmic reticulum (SR), containing ryanodine receptors (RyRs), and the sarcolemma, containing voltage- and Ca(2+)-activated K(+) (BK) channels. These junctional microdomains promote hyperpolarization, reduced Ca(in), and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca(2+)-activated Cl(-) channels, and promotes the opposite (depolarization, increased Ca(in), and contraction). The model includes three additional compartments: the sarcoplasm, the central SR lumen, and the peripheral SR lumen. It incorporates 37 protein components. In addition to pressure, the model accommodates inputs of ?- and ?-adrenergic agonists, ATP, 11,12-epoxyeicosatrienoic acid, and nitric oxide (NO). The parameters of the equations were adjusted to obtain a close fit to reported Vm and Ca(in) as functions of pressure, which have been determined in cerebral arteries. The simulations were insensitive to ± 10% changes in most of the parameters. The model also simulated the effects of inhibiting RyR, BK, or voltage-activated Ca(2+) channels on Vm and Ca(in). Deletion of BK ?1 subunits is known to increase arterial-SM tension. In the model, deletion of ?1 raised Ca(in) at all pressures, and these increases were reversed by NO.

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Intravascular pressure enhances the abundance of functional Kv1.5 channels at the surface of arterial smooth muscle cells.

Publications

Intravascular pressure enhances the abundance of functional Kv1.5 channels at the surface of arterial smooth muscle cells.

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