Cerebrovascular endothelin-1 hyper-reactivity is associated with transient receptor potential canonical channels 1 and 6 activation and delayed cerebral hypoperfusion after forebrain ischaemia in rats

Johansson, Sara Ellinor; Andersen, X. E. D. R.; Hansen, Rasmus Hvass; Povlsen, Gro Klitgaard; Edvinsson, Lars

doi:10.1111/apha.12519

Cited by 23 publications

(20 citation statements)

References 31 publications

(50 reference statements)

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“…These cardioprotective effects may be due to improved blood flow to ischemic tissue during hypoxia since GsMTx4 causes vascular smooth muscle relaxation by both decreasing mechanically activated excitatory cation currents [110, 111] and down regulation of endothelin-1 stimulated increase in arterial resistance [112, 113]. It may also affect fibroblast conductive properties which are known to play a role in generation of arrhythmias following ischemia [114, 115].…”

Section: Therapeutic Potential Of Gsmtx4mentioning

confidence: 99%

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

Suchyna

2017

Progress in Biophysics and Molecular Biology

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Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4’s mechanism of action. However, questions remain regarding Piezo’s role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4’s inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K+ selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy.

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Section: Therapeutic Potential Of Gsmtx4mentioning

confidence: 99%

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

Suchyna

2017

Progress in Biophysics and Molecular Biology

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“…Based on their amino acid sequences and functional similarities, the TRPC family can be divided into 4 groups: TRPC1, TRPC2, TRPC4/5, and TRPC3/6/7. Studies have demonstrated that TRPC6 channel has a critical role in promoting neuronal survival against cerebral ischemic injury 13–15 . Sossin et al .…”

Section: Introductionmentioning

confidence: 99%

The Role of TRPC6 in the Neuroprotection of Calycosin Against Cerebral Ischemic Injury

Guo

et al. 2017

Sci Rep

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Our previous studies have provided evidences that calycosin can protect the brain from ischemia/reperfusion injury, but its mechanisms is not fully understand. Transient receptor potential canonical 6 (TRPC6) has a critical role in promoting neuronal survival against cerebral ischemic injury. The aim of the present study is to test whether calycosin protects against cerebral ischemic injury through TRPC6-CREB pathway. In vivo, rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h and then treated with different doses of calycosin at the onset of reperfusion. In vitro, primary cultured neurons were treated by calycosin, then exposed to 2 h oxygen glucose deprivation (OGD) followed by 24 h reoxygenation. Our results showed that treatment with calycosin protected against ischemia-induced damages by increasing TRPC6 and P-CREB expression and inhibiting calpain activation. The neuroprotection effect of calycosin was diminished by inhibition or knockdown of TRPC6 and CREB. These findings indicated that the potential neuroprotection mechanism of calycosin was involved with TRPC6-CREB pathway.

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“…The increased expression of ET B and 5‐HT 1B receptors in the VSMCs of the cerebral pial arteries resulted in an increased vascular contractility correlating with cerebral hypoperfusion of the forebrain (Johansson et al . , ). Furthermore, plasma, cerebrospinal fluid and brain parenchyma concentrations of endothelin‐1 (ET‐1) and brain parenchyma concentrations of 5‐hydroxytryptamine (5‐HT) were previously found to increase after cerebral ischaemia (Zervas et al .…”

mentioning

confidence: 99%

Enhanced contractility of intraparenchymal arterioles after global cerebral ischaemia in rat – new insights into the development of delayed cerebral hypoperfusion

et al. 2017

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Cerebrovascular endothelin-1 hyper-reactivity is associated with transient receptor potential canonical channels 1 and 6 activation and delayed cerebral hypoperfusion after forebrain ischaemia in rats

Cited by 23 publications

References 31 publications

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

The Role of TRPC6 in the Neuroprotection of Calycosin Against Cerebral Ischemic Injury

Enhanced contractility of intraparenchymal arterioles after global cerebral ischaemia in rat – new insights into the development of delayed cerebral hypoperfusion

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