Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery

Medhurst, Andrew D.; Rennie, Gillian; Chapman, C.G.; Meadows, Helen; Duckworth, Malcolm; Kelsell, Rosemary E.; Gloger, Israel I.; Pangalos, Menelas N.

doi:10.1016/s0169-328x(00)00263-1

Cited by 285 publications

(232 citation statements)

References 34 publications

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“…(2) The effects of TBI on the LDP of the contused and periimpacted cortex were not significantly different, suggesting that the presence or absence of TREK-1 does not affect changes in blood flow after TBI. TREK-1 channels are abundantly expressed presynaptically and postsynaptically throughout the brain (Fink et al, 1996;Honore, 2007;Medhurst et al, 2001;Talley et al, 2001). The areas of expression include those areas directly affected by the TBI including hippocampus, cerebral cortex, and caudate putamen in mice (Fink et al, 1996;Medhurst et al, 2001;Talley et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury in Mice Lacking the K Channel, TREK-1

Namiranian

Brink

Goodman

et al. 2010

J Cereb Blood Flow Metab

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The purpose of this study was to determine whether the potassium channel, TREK-1, was neuroprotective after traumatic brain injury (TBI). Since there are no selective blockers, we used TREK-1 knockout (KO) mice for our study. Wild-type (WT) and TREK-1 KO mice were anesthetized and subjected to controlled-cortical impact injury (deformation of the brain by 1.5 mm by a 3-mm diameter rod traveling at a 3 m/s). Laser Doppler perfusion (LDP) decreased by B80% in the injured cortex and remained at that level in both WT and TREK-1 KO mice (n = 10 and 11, respectively). Laser Doppler perfusion decreased by 50% to 60% in cortical areas directly adjacent to the site of injury. There were no statistical differences in LDP between genotype. The contusion volume, determined 15 days after the TBI using hematoxylin and eosin-stained coronal brain sections, was 4.1 ± 0.8 (n = 10) and 5.1±0.5 (n = 11) mm 3 for WT and TREK-1 KO, respectively (not significant, P = 0.34). Cell counts of viable neurons in the CA1 and CA3 regions of the hippocampus were similar between WT and TREK-1 KO mice (P = 0.51 and 0.84 for CA1 and CA3, respectively). We conclude that TREK-1 expression does not provide brain protection after TBI.

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Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury in Mice Lacking the K Channel, TREK-1

Namiranian

Brink

Goodman

et al. 2010

J Cereb Blood Flow Metab

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“…KCNK7 transcript has been detected by RT-PCR in many areas of the human central nervous system including cerebellum, cortex, hippocampus and spinal cord [18]. It was also identified in mouse brain by the Allen Brain Atlas (http://www.brain-map.org/welcome.do); KCNK7 transcript can be seen at low to intermediate levels in choroid plexus within the lateral ventricle, third ventricle and lateral recess of the fourth ventricle.…”

Section: Discussionmentioning

confidence: 99%

“…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]. However, its sensitivity to the effects of anesthetics has not been determined because it has not been functionally expressed in heterologous expression systems [20].…”

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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“…TREK-1 channels are highly expressed in the human CNS (Medhurst et al, 2001) and are targets for pharmacologically important compounds like general anesthetics and neuroprotective drugs like riluzole (Franks and Honore, 2004). TREK-1 is potently inhibited by neurotransmitters that produce an increase in intracellular cAMP and also by those that activate the Gq protein pathway suggesting that probably TREK-1 channels have a central role in the control of excitability by neurotransmitters (Patel et al, 1998;Chemin et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced leak channel activity hyperpolarizes neurons, leading to decreased action potential firing; in contrast, leak suppression results in membrane depolarization and excitation (Sirois et al, 2000). TREK-1 is an important member of this family, and is expressed through out the central nervous system (Fink et al, 1996;Lauritzen et al, 2000;Hervieu et al, 2001;Medhurst et al, 2001;Talley et al, 2001). TREK-1 has been proposed to be an important pharmacological target for general anesthetics (Franks and Honore, 2004).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human TREK-1 channels by caffeine and theophylline

Harinath

Sikdar

2005

Epilepsy Research

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Caffeine (1,3,7-trimethylxanthine) and theophylline (1,3-dimethylxanthine) are used for therapeutic purposes and can cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. TWIK-related K + channels (TREK-1) are highly expressed in the human central nervous system and have a major role in the control of neuronal excitability by regulating the resting membrane potential. In view of their physiological significance, inhibition of TREK-1 channels may be implicated in caffeine-and theophylline-induced seizures. We thus investigated, using whole-cell patch-clamp technique, modulation of hTREK-1 channels expressed in Chinese hamster ovary (CHO) cells by caffeine and theophylline. Caffeine and theophylline produced reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC 50 ) for caffeine and theophylline were 377 ± 54 M and 486 ± 76 M, respectively. Caffeine and theophylline depolarized the membrane potential of CHO TREK-1 cells in a reversible and concentrationdependent manner. Inhibition by caffeine (5 mM) and theophylline (2 mM) was attenuated in TREK-1 channels with mutation of the PKA consensus sequence at serine 348, suggesting the involvement of cAMP/PKA pathway in the inhibitory process. Inhibition of TREK-1 channels and consequent membrane depolarization may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline.

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Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery

Cited by 285 publications

References 34 publications

Traumatic Brain Injury in Mice Lacking the K Channel, TREK-1

Traumatic Brain Injury in Mice Lacking the K Channel, TREK-1

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

Inhibition of human TREK-1 channels by caffeine and theophylline

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