Evidence for two-pore domain potassium channels in rat cerebral arteries

Bryan, Robert M.; You, Junping; Phillips, Sharon C.; Andresen, Jon; Lloyd, Elisabeth A.; Rogers, Paul A.; Dryer, Stuart E.; Marrelli, Sean P.

doi:10.1152/ajpheart.01377.2005

Cited by 55 publications

(54 citation statements)

References 43 publications

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“…23 Recent work has provided evidence for the presence of two-pore domain K ϩ channels in rat mesenteric, cerebral, and pulmonary arteries, suggesting that some of these channels could play a physiological role in regulating basal membrane potential and tone in these vessels. 9,10,24 This article shows that TREK-1 channels are well expressed in the basilar vasculature of both rats and mice whereas they are essentially absent in the carotid artery. There is a strict parallelism between the localization of TREK-1 channels in these different arteries and the vasodilation effect of PUFAs, which is observed only with basilar but not carotid arteries.…”

Section: Discussionmentioning

confidence: 90%

“…A previous report shows the presence of the TREK-1 channel in mesenteric rat arteries but not in pulmonary arteries, suggesting that the expression pattern of this channel depends on the type of arteries. 9 On the other hand, Bryan et al report the presence of K 2P channels in vascular smooth muscle cells of rat middle cerebral arteries, 10 and we have recently described the crucial role of the TREK-1 channel in both mesenteric arteries and skin microvessels. 11 In these vessels the TREK-1 deletion leads to a dysfunction of endothelial factors production, particularly NO, that are responsible for smooth muscle relaxation.…”

mentioning

confidence: 72%

“…25 The second one would involve a direct effect of PUFAs on smooth muscle creating an hyperpolarizing-relaxing response. Bryan et al 10 have recently demonstrated the presence of an "atypical" K ϩ channel, insensitive to classical potassium channels inhibitors, with biophysical properties similar to K 2P channels of the TREK-1 family, that, in response to arachidonic acid, hyperpolarizes smooth muscle and dilates MCA artery. 10 The NO-independent PUFA-induced vasodilation reported here is a particularly interesting observation considering the drastic alteration of endothelium-dependent NO-mediated vasodilation in cerebral arteries after stroke.…”

Section: Circulation Research July 20 2007mentioning

confidence: 99%

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Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel

Blondeau

Pétrault

Manta

et al. 2007

Circulation Research

112

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Abstract-Vessel occlusion is the most frequent cause for impairment of local blood flow within the brain resulting in neuronal damage and is a leading cause of disability and death worldwide. Polyunsaturated fatty acids and especially ␣-linolenic acid improve brain resistance against cerebral ischemia. The purpose of the present study was to evaluate the effects of polyunsaturated fatty acids and particularly ␣-linolenic acid on the cerebral blood flow and on the tone of vessels that regulate brain perfusion. ␣-Linolenic acid injections increased cerebral blood flow and induced vasodilation of the basilar artery but not of the carotid artery. The saturated fatty acid palmitic acid did not produce vasodilation. This suggested that the target of the polyunsaturated fatty acids effect was the TREK-1 potassium channel. We demonstrate the presence of this channel in basilar but not in carotid arteries. We show that vasodilations induced by the polyunsaturated fatty acid in the basilar artery as well as the laser-Doppler flow increase are abolished in TREK-1 Ϫ/Ϫ mice. Altogether these data indicate that TREK-1 activation elicits a robust dilation that probably accounts for the increase of cerebral blood flow induced by polyunsaturated fatty acids such as ␣-linolenic acid or docosahexanoic acid. They suggest that the selective expression and activation of TREK-1 in brain collaterals could play a significant role in the protective mechanisms of polyunsaturated fatty acids against stroke by providing residual circulation during ischemia. (Circ Res. 2007;101:176-184.) Key Words: cerebral ischemia Ⅲ ␣-linolenic acid Ⅲ CBF Ⅲ vasodilatation Ⅲ two pore-domains channel TREK-1 A fter stroke, the function of cerebral arteries is critical to maintain cerebral perfusion and preserve neuronal integrity. The duration and intensity of the blood flow deficit are associated with the severity of brain damage. The level of cerebral blood flow (CBF) in brain tissue is coupled to an evident extent with vascular function and beyond neuronal consequences. It is well known that cerebral ischemia is associated with functional impairment of vascular tone within the occluded artery. 1 Polyunsaturated fatty acids (PUFAs) and particularly ␣-linolenic acid (ALA) and docosahexanoic acid (DHA) are potent protectors against focal and global ischemia. [2][3][4] The molecular mechanism of PUFA-induced neuroprotection has been recently clarified. 5 The main PUFA target seems to be the potassium channel, TREK-1, which belongs to the new family of two-pore domain potassium channels (K 2P ) and is known to be potently activated by PUFA. 6 -8 The importance of the TREK-1 channel in cerebral protection against ischemia has been validated by the fact that the protective effects of PUFA are drastically decreased in TREK-1-deficient mice. 5 The vascular wall represents the primary compartment of ischemic stroke. PUFA application confers neuronal protection, 2-4 but little is known about TREK-1 channel in cerebral vessels. A previous report shows the presence ...

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 72%

Section: Circulation Research July 20 2007mentioning

confidence: 99%

See 1 more Smart Citation

Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel

Blondeau

Pétrault

Manta

et al. 2007

Circulation Research

112

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“…The whole-cell patch-clamp configuration was used for measurements of whole-cell currents in freshly isolated SMC using a MultiClamp 700B amplifier (Axon Instruments) and pCLAMP 10 software (Axon Instruments, Union City, CA), as reported previously (4). Patch electrodes were pulled from borosilicate glass (1.65 outer diameter, 1.28 inner diameter; Warner Instruments) and polished to a pipette resistance of ϳ2 M⍀.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

Chen¹,

Crossland²,

Noorani³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) inhibits transient receptor potential channel 3 (TRPC3) channels via a PKG-dependent mechanism. We sought to determine 1) whether NO inhibition of TRPC3 occurs in freshly isolated smooth muscle cells (SMC); and 2) whether NO inhibition of TRPC3 channels contributes to NO-mediated vasorelaxation. We tested these hypotheses in freshly isolated rat carotid artery (CA) SMC using patch clamp and in intact CA by vessel myograph. We demonstrated TRPC3 expression in whole CA (mRNA and protein) that was localized to the smooth muscle layers. TRPC1 protein was also expressed and coimmunoprecipitated with TRPC3. Whole cell patch clamp demonstrated nonselective cation channel currents that were activated by UTP (60 M) and completely inhibited by a TRPC channel inhibitor, La 3ϩ (100 M). The UTP-stimulated current (IUTP) was also inhibited by intracellular application of anti-TRPC3 or anti-TRPC1 antibody, but not by anti-TRPC6 or anti-TRPC4 control antibodies. We next evaluated the NO signaling pathway on I UTP. Exogenous NO [(Z)-1-{N-methyl-N-[6(N-methylammoniohexyl)-amino]}diazen-1-ium-1,2-diolate (MAHMA NONOate)] or a cellpermeable cGMP analog (8-bromo-cGMP) significantly inhibited I UTP . Preapplication of a PKG inhibitor (KT5823) reversed the inhibition of MAHMA NONOate or 8-bromo-cGMP, demonstrating the critical role of PKG in NO inhibition of TRPC1/TRPC3. Intact CA segments were contracted with UTP (100 M) in the presence or absence of La 3ϩ (100 M) and then evaluated for relaxation to an NO donor, sodium nitroprusside (1 nM to 1 M). Relaxation to sodium nitroprusside was significantly reduced in the La 3ϩ treatment group. We conclude that freshly isolated SMC express TRPC1/TRPC3 channels and that these channels are inhibited by NO/cGMP/PKG. Furthermore, NO contributes to vasorelaxation by inhibition of La 3ϩ -sensitive channels consistent with TRPC1/TRPC3. transient receptor potential channel; protein kinase G; transient receptor potential 3; transient receptor potential 1 THE CANONICAL TRANSIENT RECEPTOR potential channels (TRPCs) are nonselective cation channels that have been demonstrated to play a variety of roles in regulation of vascular tone (23). TRPC3 is one of the less well-characterized members of the TRPC family (TRPC1-7) within the vasculature. Nevertheless, TRPC3 has recently been shown to be involved in receptor-mediated constriction within the smooth muscle cells (SMCs) of cerebral arteries (18). Activation of the TRPC3 channel permits Ca 2ϩ and Na ϩ entry into the cell; however, the major mechanism of Ca 2ϩ entry in SMC is thought to be secondary to Na ϩ entry and smooth muscle depolarization (18). Depolarization from Na ϩ entry leads to activation of L-type Ca 2ϩ channels with subsequent Ca 2ϩ entry and smooth muscle contraction.Nitric oxide (NO) is well known as a vasodilator. However, the mechanism by which NO promotes smooth muscle relaxation is still incompletely resolved. At this time, it is believed that NO leads to smooth muscle relaxation by multiple pathways, including acti...

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“…KCNK7 belongs to the inward rectifier subfamily of K 2P channels. It is most homologous to two other K 2P channels, TWIK-1 and TWIK-2, that are expressed in the cerebral circulation [1] cortex and hippocampus [3,12]. KCNK7 is also expressed in relatively high abundance in the cerebral cortex, hippocampus, nucleus accumbens and spinal cord [18].…”

Section: Introductionmentioning

confidence: 99%

Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity

Yost¹,

Oh²,

Eger³

et al. 2008

Behavioural Brain Research

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The molecular site of action for volatile anesthetics remains unknown despite many years of study. Members of the K 2P potassium channel family, whose currents are potentiated by volatile anesthetics have emerged as possible anesthetic targets. In fact, a mouse model in which the gene for TREK-1 (KCNK2) has been inactivated shows resistance to volatile anesthetics. In this study we tested whether inactivation of another member of this ion channel family, KCNK7, in a knockout mouse displayed altered sensitivity to the anesthetizing effect of volatile anesthetics.KCNK7 knockout mice were produced by standard gene inactivation methods. Heterozygous breeding pairs produced animals that were homozygous, heterozygous or wildtype for the inactivated gene. Knockout animals were tested for movement in response to noxious stimulus (tail clamp) under varying concentrations of isoflurane, sevoflurane and desflurane to define the minimum alveolar concentration (MAC) preventing movement.Mice homozygous for inactivated KCNK7 were viable and indistinguishable in weight, general development and behavior from heterozygotes or wildtype littermates. Knockout mice (KCNK7 −/ −) displayed no difference in MAC for the three volatile anesthetics compared to heterozygous (+/ −) or wildtype (+/+) littermates.Because inactivation of KCNK7 does not alter MAC, KCNK7 may play only a minor role in normal CNS function or may have had its function compensated for by other inhibitory mechanisms. Additional studies with transgenic animals will help define the overall role of the K 2P channels in normal neurophysiology and in volatile anesthetic mechanisms.

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Evidence for two-pore domain potassium channels in rat cerebral arteries

Cited by 55 publications

References 43 publications

Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel

Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity

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