BL-1249 [(5,6,7,8-Tetrahydro-naphthalen-1-yl)-[2-(1<i>H</i>-tetrazol-5-yl)-phenyl]-amine]: A Putative Potassium Channel Opener with Bladder-Relaxant Properties

Tertyshnikova, Svetlana; Knox, Ronald J.; Plym, Mary Jane; Thalody, George; Griffin, C. L.; Neelands, Torben R.; Harden, David G.; Signor, Laura J.; Weaver, David T.; Myers, Robert A.; Lodge, Nicholas J.

doi:10.1124/jpet.104.078592

Cited by 51 publications

(39 citation statements)

References 35 publications

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“…, another fenamate-like structure and a putative activator of TREK1-like currents in human bladder myocytes (Tertyshnikova et al, 2005), also activated recombinantly expressed TREK1. Interestingly, BL-1249 was around 30 to 100 times more potent than FFA, with 1 mM producing a 130% 6 17% (n 5 8) enhancement ( Fig.…”

Section: Resultsmentioning

confidence: 96%

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

et al. 2014

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TWIK-related K 1 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K 1 -selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.

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Section: Resultsmentioning

confidence: 96%

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

et al. 2014

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“…When human or rat bladder myocytes were treated with the bladder relaxant BL-1249, the compound activated a leak K ϩ current with pharmacological properties of the TREK channels (314). Relatively high expression of TREK-1 was also demonstrated in human bladder cells versus aortic myocytes, in which BL-1249 failed to cause relaxation (314).…”

Section: Adaptive Relaxation Of Visceral Hollow Organsmentioning

confidence: 99%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

757

769

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Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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“…Human and mouse bladder also has TREK -1 K + channels (Tertyshnikova et al 2005 ;Baker et al 2010) and so the function and modulatory mechanism of this channel needs to be further examined.…”

Section: Discussionmentioning

confidence: 99%

Swelling-activated and arachidonic acid-induced currents are TREK-1 in rat bladder smooth muscle cells

Fukasaku

Kimura

Yamaguchi

2016

FJMS

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Using the perforated patch voltage clamp, we investigated swelling -activated ionic channels (SACs) in rat urinary bladder smooth muscle cells. Hypo -osmotic (60%) bath solution increased a membrane current which was inhibited by the SAC inhibitor, gadolinium. The reversal potential of the hypotonicity -induced current shifted in the positive direction by increasing external K + concentration. The hypotonicity -induced current was inhibited by extracellular acidic pH, phorbol ester and forskolin. These pharmacological properties are identical to those of arachidonic acid -induced current present in these cells, suggesting the presence of TREK -1, a four -transmembrane two pore domain K + channel. Using RT -PCR we screened rat bladder smooth muscles and cerebellum for expression of TREK -1, TREK -2 and TRAAK mRNAs. Only TREK -1 mRNA was expressed in the bladder, while all three were expressed in the cerebellum. We conclude that a mechanosensitive K + channel is present in rat bladder myocytes, which is activated by arachidonic acid and most likely is TREK -1. This K + channel may have an important role in the regulation of bladder smooth muscle tone during urine storage.

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BL-1249 [(5,6,7,8-Tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: A Putative Potassium Channel Opener with Bladder-Relaxant Properties

Cited by 51 publications

References 35 publications

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Swelling-activated and arachidonic acid-induced currents are TREK-1 in rat bladder smooth muscle cells

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BL-1249 [(5,6,7,8-Tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: A Putative Potassium Channel Opener with Bladder-Relaxant Properties

Cited by 51 publications

References 35 publications

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

Swelling-activated and arachidonic acid-induced currents are TREK-1 in rat bladder smooth muscle cells

Contact Info

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Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels