TRPC5 channels participate in pressure-sensing in aortic baroreceptors

Lau, Eva On-Chai; Shen, Bing; Wong, Ching On; Tjong, Yung Wui; Lo, Chun-Yin; Wang, Hui Chuan; Huang, Yü; Yung, Wing-Ho; Chen, Yangchao; Fung, Man Lung; Rudd, John A.; Yao, Xiaoqiang

doi:10.1038/ncomms11947

Cited by 63 publications

(77 citation statements)

References 37 publications

(66 reference statements)

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“…Although observational clinical studies and changes detected in genetically or pharmacologically modified rodents and/or human tissue suggest multiple physiological roles of TRPC1/4/5 channels (Bon & Beech, 2013;Bröker-Lai et al, 2017;Lau et al, 2016;Lepannetier et al, 2018), disruption of the Trpc4/5 genes (Suresh Babu, Wojtowicz, Birnbaumer, Hecker, & Cattaruzza, 2012) and global expression of a dominant-negative mutant TRPC5 (Sukumar et al, 2012) do not cause catastrophic phenotypes. However, the involvement of TRPC1/4/5 channels in various human diseases-including CNS disorders, kidney disease, cancer, cardiovascular disease, and complications of diabetes -has led these channels to emerge as potential therapeutic targets (Bon & Beech, 2013;Gaunt, Vasudev, & Beech, 2016;Just et al, 2018;Minard et al, 2018;Zhou et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Minard

Bauer

Chuntharpursat‐Bon

et al. 2019

British J Pharmacology

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Background and Purpose The TRPC1, TRPC4, and TRPC5 proteins form homotetrameric or heterotetrameric, calcium‐permeable cation channels that are involved in various disease states. Recent research has yielded specific and potent xanthine‐based TRPC1/4/5 inhibitors. Here, we investigated the possibility of xanthine‐based activators of these channels. Experimental Approach An analogue of the TRPC1/4/5 inhibitor Pico145, AM237, was synthesized and its activity was investigated using HEK cells overexpressing TRPC4, TRPC5, TRPC4–C1, TRPC5–C1, TRPC1:C4 or TRPC1:C5 channels, and in A498 cells expressing native TRPC1:C4 channels. TRPC1/4/5 channel activities were assayed by measuring intracellular concentration of Ca2+ ([Ca2+]i) and by patch‐clamp electrophysiology. Selectivity of AM237 was tested against TRPC3, TRPC6, TRPV4, or TRPM2 channels. Key Results AM237 potently activated TRPC5:C5 channels (EC50 15–20 nM in [Ca2+]i assay) and potentiated their activation by sphingosine‐1‐phosphate but suppressed activation evoked by (−)‐englerin A (EA). In patch‐clamp studies, AM237 activated TRPC5:C5 channels, with greater effect at positive voltages, but with lower efficacy than EA. Pico145 competitively inhibited AM237‐induced TRPC5:C5 activation. AM237 did not activate TRPC4:C4, TRPC4–C1, TRPC5–C1, TRPC1:C5, and TRPC1:C4 channels, or native TRPC1:C4 channels in A498 cells, but potently inhibited EA‐dependent activation of these channels with IC50 values ranging from 0.9 to 7 nM. AM237 (300 nM) did not activate or inhibit TRPC3, TRPC6, TRPV4, or TRPM2 channels. Conclusions and Implications This study suggests the possibility for selective activation of TRPC5 channels by xanthine derivatives and supports the general principle that xanthine‐based compounds can activate, potentiate, or inhibit these channels depending on subunit composition.

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Section: Introductionmentioning

confidence: 99%

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Minard

Bauer

Chuntharpursat‐Bon

et al. 2019

British J Pharmacology

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“…Arterial baroreceptors are known to possess heterogenic mechanosensing ion channel composition (Drummond et al 1998;Lu et al 2009;Lau et al 2016;Zeng et al 2018) and afferent innervation (i.e. type A myelinated, type C unmyelinated), which differ in their responsivity to blood pressure stimuli (absolute pressure vs. relative pressure change) (Seagard et al 1990) and influence over nucleus tractuus solitarii neurons (Seagard et al 1990, Rogers et al 1993, 1996Andresen & Kunze, 1994;Hayward & Felder, 1995;Dean & Seagard, 1997;Zhang & Mifflin, 2000;Kolpakova et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Arterial baroreflex regulation of muscle sympathetic nerve activity at rest and during stress

Incognito

Duplea

Lee

et al. 2019

The Journal of Physiology

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Key points The arterial baroreflex controls vasoconstrictor muscle sympathetic nerve activity (MSNA) in a negative feedback manner by increasing or decreasing activity during spontaneous blood pressure falls or elevations, respectively. Spontaneous sympathetic baroreflex sensitivity is commonly quantified as the slope of the relationship between MSNA burst incidence or strength and beat‐to‐beat variations in absolute diastolic blood pressure. We assessed the relationships between blood pressure inputs related to beat‐to‐beat blood pressure change or blood pressure rate‐of‐change (variables largely independent of absolute pressure) and MSNA at rest and during exercise and mental stress. The number of participants with strong linear relationships between MSNA and beat‐to‐beat diastolic blood pressure change variables or absolute diastolic blood pressure were similar at rest, although during stress the beat‐to‐beat diastolic blood pressure change variables were superior. Current methods may not fully characterize the capacity of the arterial baroreflex to regulate MSNA. Abstract Spontaneous sympathetic baroreflex sensitivity (sBRS) is commonly quantified as the slope of the relationship between variations in absolute diastolic blood pressure (DBP) and muscle sympathetic nerve activity (MSNA) burst incidence or strength. This relationship is well maintained at rest but not during stress. We assessed whether sBRS could be calculated at rest and during stress (static handgrip, rhythmic handgrip, mental stress) using blood pressure variables that quantify relative change: beat‐to‐beat DBP change (ΔDBP), ΔDBP rate‐of‐change (ΔDBP rate), pulse pressure (PP) and PP rate‐of‐change (PP rate). Sixty‐six healthy participants underwent continuous measures of blood pressure (finger photoplethysmography) and multi‐unit MSNA (microneurography). At rest, absolute DBP (91%), ΔDBP (97%) and ΔDBP rate (97%) each yielded higher proportions of participants with strong linear relationships (r ≥ 0.6) with MSNA burst incidence compared to PP (57%) and PP rate (56%) and produced similar sBRS slopes (DBP: −4.5 ± 2.0 bursts 100 heartbeats–1/mmHg; ΔDBP: −5.0 ± 2.1 bursts 100 heartbeats–1/ΔmmHg; ΔDBP rate: −4.9 ± 2.2 bursts 100 heartbeats–1/ΔmmHg s–1; P > 0.05). During stress, ΔDBP (74%) and ΔDBP rate (74%) yielded higher proportions of strong linear relationships with MSNA burst incidence than absolute DBP (43%), PP (46%) and PP rate (49%) (all P < 0.05). The absolute DBP associated with a 50% chance of a MSNA burst (T50) was shifted rightward during static handgrip (Δ+15 ± 11 mmHg, P < 0.001) and mental stress (Δ+11 ± 7 mmHg, P < 0.001); however, the ΔDBP T50 was shifted rightward during static handgrip (Δ+2.5 ± 3.7 mmHg, P = 0.009) but not mental stress (Δ0.0 ± 4.4 mmHg, P = 0.99). These findings suggest that calculating sBRS using absolute DBP alone may not adequately characterize arterial baroreflex regulation of MSNA, particularly during stress.

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“…It is accepted that endogenous regulatory factors can regulate the baroreceptor by affecting receptor nerve terminals directly targeting voltage‐dependent ion channels, such as transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential cation channel subfamily C member 5 (TRPC5), and acid‐sensing ion channel 2 (ASIC2) . TRPV1, the first member of the transient receptor potential family to be discovered, is distributed mainly in sensory nerve endings and mediates thermal effect and pain afferent .…”

Section: Introductionmentioning

confidence: 99%

Endogenous Hydrogen Sulfide Enhances Carotid Sinus Baroreceptor Sensitivity by Activating the Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1) Channel

Wen

Liao

Huang

et al. 2017

JAHA

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BackgroundWe aimed to investigate the regulatory effects of hydrogen sulfide (H2S) on carotid sinus baroreceptor sensitivity and its mechanisms.Methods and ResultsMale Wistar‐Kyoto rats and spontaneously hypertensive rats (SHRs) were used in the experiment and were given an H2S donor or a cystathionine‐β‐synthase inhibitor, hydroxylamine, for 8 weeks. Systolic blood pressure and the cystathionine‐β‐synthase/H2S pathway in carotid sinus were detected. Carotid sinus baroreceptor sensitivity and the functional curve of the carotid baroreceptor were analyzed using the isolated carotid sinus perfusion technique. Effects of H2S on transient receptor potential cation channel subfamily V member 1 (TRPV1) expression and S‐sulfhydration were detected. In SHRs, systolic blood pressure was markedly increased, but the cystathionine‐β‐synthase/H2S pathway in the carotid sinus was downregulated in comparison to that of Wistar‐Kyoto rats. Carotid sinus baroreceptor sensitivity in SHRs was reduced, demonstrated by the right and upward shift of the functional curve of the carotid baroreceptor. Meanwhile, the downregulation of TRPV1 protein was demonstrated in the carotid sinus; however, H2S reduced systolic blood pressure but enhanced carotid sinus baroreceptor sensitivity in SHRs, along with TRPV1 upregulation in the carotid sinus. In contrast, hydroxylamine significantly increased the systolic blood pressure of Wistar‐Kyoto rats, along with decreased carotid sinus baroreceptor sensitivity and reduced TRPV1 protein expression in the carotid sinus. Furthermore, H2S‐induced enhancement of carotid sinus baroreceptor sensitivity of SHRs could be amplified by capsaicin but reduced by capsazepine. Moreover, H2S facilitated S‐sulfhydration of TRPV1 protein in the carotid sinus of SHRs and Wistar‐Kyoto rats.ConclusionsH2S regulated blood pressure via an increase in TRPV1 protein expression and its activity to enhance carotid sinus baroreceptor sensitivity.

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TRPC5 channels participate in pressure-sensing in aortic baroreceptors

Cited by 63 publications

References 37 publications

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Arterial baroreflex regulation of muscle sympathetic nerve activity at rest and during stress

Endogenous Hydrogen Sulfide Enhances Carotid Sinus Baroreceptor Sensitivity by Activating the Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1) Channel

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