The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential

Simard, Christophe; Hof, Thomas; Keddache, Zakia; Launay, Pierre; Guinamard, Romain

doi:10.1016/j.yjmcc.2013.01.019

Cited by 78 publications

(83 citation statements)

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“…It has previously been demonstrated that TRPM4 mRNA is widely expressed in numerous types of tissue, the highest mRNA transcript levels being found in the prostate and the intestines [13]. Whereas the physiological function of TRPM4 in the prostate is unknown, it is involved in such diverse functions as depolarisation of vascular smooth muscle cells [25], regulation of sinus rhythm of the heart [26] and the process of cell death through Na + influx [27]. Furthermore, TRPM4 expression is upregulated in an aggressive form of large B-cell non-Hodgkin lymphoma [28], and high expression has been found to correlate with tumour progression and metastatic disease [18,28].…”

Section: Discussionmentioning

confidence: 99%

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

et al. 2015

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BACKGROUND Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP). MATERIAL AND METHODS The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody. Staining intensity was recorded by two independent observers using a four-tired semi-quantitative grading system (0, 1+, 2+, 3+) converted into H-scores. Interobserver agreement was calculated by linear weighted kappa statistics. The association between staining intensity and BR was analysed using the Kaplan-Meier estimator and uni-and multiple Cox proportional hazard regression models. RESULTS Significantly higher staining intensity was found in PCa glands compared to benign glands (p < 0.001). The concordance rate in TRPM4 staining intensities for benign, PIN and PCa tissue ranged from 86.0 to 91.5 %, corresponding to linear weighted kappa values of 0.566-0.789. After adjusting for patient and tumour characteristics, patients with a higher staining intensity in PCa glands compared to matched benign glands and an H-score equal to or above the median had an increased risk of BR (HR 1.79-2.62; p = 0.01-0.03 for the two observers) when compared to patients with a lower staining intensity. CONCLUSIONS TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue, with highest staining intensities found in PCa. Overexpression of TRPM4 in PCa (combination of high staining intensity and a high H-score) is associated with increased risk of BR after RP.

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Section: Discussionmentioning

confidence: 99%

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

et al. 2015

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“…Thus, NCX KO SAN burst firing may be modulated by the same Ca-activated channels found in neurons and chromaffin cells. Ca activation of TRPM4 channels may also contribute to the EADs we recorded in the NCX KO SAN preparation (43).…”

Section: Parallel Mechanisms Between Ncx Ko Pacemaker Activity and Burstmentioning

confidence: 93%

Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice

Torrente¹,

Zhang²,

Zaini³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

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In sinoatrial node (SAN) cells, electrogenic sodium-calcium exchange (NCX) is the dominant calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent. Voltage mapping revealed disorganized and arrhythmic depolarizations within the NCX KO SAN that failed to propagate into the atria. LSCM revealed intermittent bursts of Ca transients. Bursts were accompanied by rising diastolic Ca, culminating in long pauses dominated by Ca waves. The L-type Ca channel agonist BayK8644 reduced the rate of Ca transients and inhibited burst generation in the NCX KO SAN whereas the Ca buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl ester) (BAPTA AM) did the opposite. These results suggest that cellular Ca accumulation hinders spontaneous depolarization in the NCX KO SAN, possibly by inhibiting L-type Ca currents. The funny current (I f ) blocker ivabradine also suppressed NCX KO SAN automaticity. We conclude that pacemaker activity is present in the NCX KO SAN, generated by a mechanism that depends upon I f . However, the absence of NCX-mediated depolarization in combination with impaired Ca efflux results in intermittent bursts of pacemaker activity, reminiscent of human sinus node dysfunction and "tachy-brady" syndrome.sinoatrial node | sodium-calcium exchange | pacemaker activity | arrhythmia | intracellular calcium P hysiological heart rhythm originates in the sinoatrial node (SAN), a cluster of specialized pacemaker cells located on the endocardial surface of the right atrium (RA). SAN dysfunction (SND) leads to serious arrhythmias characterized by pathological pauses, often alternating with rapid heart rates or atrial fibrillation (1). Each year in the United States, close to 200,000 patients affected with SAN disease require surgical implantation of an electronic pacemaker (2). Therefore, advances in our understanding of SAN pacemaker activity are essential for developing new therapies to avoid this costly procedure and its related morbidity.In SAN pacemaker cells, action potentials (APs) are thought to be triggered by spontaneous diastolic depolarization (SDD) produced by a coupled system of cellular "clocks" (3). The first clock, known as the "membrane clock," initiates SDD in response to inward funny current (I f ) carried mostly by HCN4 channels (4) although other ion channels, like voltage-dependent Ca channels, have also been implicated (5). The second (and more controversial) clock is referred to as the "Ca clock." This clock produces a depolarizing current in late diastole when local Ca released by ryanodine receptors (RyRs) on the sarcoplasmic reticulum (SR) is extruded by the e...

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“…by guest on May 11, 2018 http://circres.ahajournals.org/ Downloaded from January 17, 2014 in atrial myocytes. 13 Using laser-microdissected preparations, we can show Trpm4 expression unambiguously in left ventricular cardiomyocytes (Online Figure VI). To analyze functional expression of TRPM4 in ventricular myocytes, we performed whole-cell patch-clamp experiments in isolated ventricular myocytes using intra-and extracellular solutions that minimized the activity of K + channels.…”

Section: +mentioning

confidence: 94%

“…24 The time course of the TRPM4 current we report here is similar to that reported for the highly related TRPM5 channel (which has similar properties as TRPM4 but is not present in the heart) in pancreatic β-cells. 25 Recording of TRPM4-dependent single-channel currents in cell-free patches from atrial myocytes required, besides pretreatment of cells with phorbol-12-myristate-13-acetate, 1 mmol/L Ca 2+ at the intracellular side of the membrane, 13 indicating that the Ca 2+ sensitivity of the TRPM4 current is relatively low in myocytes and that TRPM4 will likely follow the increase in subcellular Ca 2+ level near the Ca 2+ release sites rather than the global Ca 2+ transient during excitation-contraction coupling. The time course of TRPM4 activity in myocytes closely resembles the time course of the subcellular Ca 2+ level in stimulated myocytes, which decays from an estimated level of 10 μmol/L within 10 ms to a concentration of ≈1 μmol/L.…”

Section: +mentioning

confidence: 99%

“…12 TRPM4-like activity has been described in sinoatrial node cells, 12 and atrial myocytes from Trpm4 −/− mice display a shorter AP. 13 Interest in the physiological role of TRPM4 in the heart has further risen with the description of mutations in the TRPM4 gene that are linked to autosomal dominant forms of cardiac conduction diseases, including progressive familial heart block type I and Brugada syndrome. [14][15][16] Heterologous overexpression of mutant channels in human embryonic kidney cells indicates that these mutations can lead to increased or decreased expression and activity of TRPM4 proteins, [14][15][16][17] which might contribute through an as yet unknown mechanism to the above-mentioned syndromes.…”

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confidence: 99%

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Increased β-Adrenergic Inotropy in Ventricular Myocardium From Trpm4 ^−/− Mice

Mathar

Kecskés

Mieren

et al. 2014

Circulation Research

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The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential

Cited by 78 publications

References 39 publications

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice

Increased β-Adrenergic Inotropy in Ventricular Myocardium From Trpm4 ^−/− Mice

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The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential

Cited by 78 publications

References 39 publications

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice

Increased β-Adrenergic Inotropy in Ventricular Myocardium From Trpm4 −/− Mice

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Increased β-Adrenergic Inotropy in Ventricular Myocardium From Trpm4 ^−/− Mice