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The involvement of TRPC3 channels in sinoatrial arrhythmias.

Ju YK, Lee BH, Trajanovska S, Hao G, Allen DG, Lei M, Cannell MB - Front Physiol (2015)

Bottom Line: We will then present some of our recent research progress in this field.Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3(-/-) mice) compared to wild type controls.We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Medical Sciences, Bosch Institute, University of Sydney Sydney, NSW, Australia.

ABSTRACT
Atrial fibrillation (AF) is a significant contributor to cardiovascular morbidity and mortality. The currently available treatments are limited and AF continues to be a major clinical challenge. Clinical studies have shown that AF is frequently associated with dysfunction in the sino-atrial node (SAN). The association between AF and SAN dysfunction is probably related to the communication between the SAN and the surrounding atrial cells that form the SAN-atrial pacemaker complex and/or pathological processes that affect both the SAN and atrial simultaneously. Recent evidence suggests that Ca(2+) entry through TRPC3 (Transient Receptor Potential Canonical-3) channels may underlie several pathophysiological conditions -including cardiac arrhythmias. However, it is still not known if atrial and sinoatrial node cells are also involved. In this article we will first briefly review TRPC3 and IP3R signaling that relate to store/receptor-operated Ca(2+) entry (SOCE/ROCE) mechanisms and cardiac arrhythmias. We will then present some of our recent research progress in this field. Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3(-/-) mice) compared to wild type controls. We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R. Activation of G-protein coupled receptors (GPCRs) signaling that is able to modulate SOCE/ROCE and Ang II induced Ca(2+) homeostasis changes in sinoatrial complex being linked to TRPC3. The results provide new evidence that TRPC3 may play a role in sinoatrial and atrial arrhythmias that are caused by GPCRs activation.

No MeSH data available.


Related in: MedlinePlus

Modulation of store-operated Ca entry (SOCE) by ET-1 and 2-APB. SOCE was induced by using cyclopiazonic acid (CPA) and low external Ca2+. The addition timing of extracellular Ca2+ change is indicated in the top panels. (A) The effect of ET-1 on SOCE induced by 10 μM CPA with 15 min incubation in Ca2+ free Tyrode's solution. (B) The effect of ET-1 on SOCE induced by 20 μM CPA with 30 min incubation in Ca2+ free Tyrode's solution. (C) The effect of 40 μM 2-APB on SOCE. 2-APB was added in the same time of reintroduction of extracellular Ca2+ after perfusion of Ca2+ free Tyrode's Solution containing 10 μM CPA. (D) The effect of 40 μM 2-APB on SOCE. 2-APB was added into the Ca2+ free Tyrode's solution with 10 μM CPA during the 15 min incubation period. The gray traces represent controls; the black traces represent the treatments with ET-1 (A,B) or 2-APB (C,D), respectively.
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Figure 4: Modulation of store-operated Ca entry (SOCE) by ET-1 and 2-APB. SOCE was induced by using cyclopiazonic acid (CPA) and low external Ca2+. The addition timing of extracellular Ca2+ change is indicated in the top panels. (A) The effect of ET-1 on SOCE induced by 10 μM CPA with 15 min incubation in Ca2+ free Tyrode's solution. (B) The effect of ET-1 on SOCE induced by 20 μM CPA with 30 min incubation in Ca2+ free Tyrode's solution. (C) The effect of 40 μM 2-APB on SOCE. 2-APB was added in the same time of reintroduction of extracellular Ca2+ after perfusion of Ca2+ free Tyrode's Solution containing 10 μM CPA. (D) The effect of 40 μM 2-APB on SOCE. 2-APB was added into the Ca2+ free Tyrode's solution with 10 μM CPA during the 15 min incubation period. The gray traces represent controls; the black traces represent the treatments with ET-1 (A,B) or 2-APB (C,D), respectively.

Mentions: After initial incubation of the SAN in Ca2+ free Tyrode's with the SR uptake blocked with CPA (10 μmol/L), reintroduction of Ca2+ (1.8 mmol/L) caused a significant Ca2+ influx (i.e., SOCE) as shown by an increase in Indo-1 ratio (Figure 4A). Importantly, peak SOCE was increased by 63 ± 10% (n = 4, P < 0.05) in the presence of ET-1, a representative trace of which is shown in Figure 4A. Addition of the membrane permeant IP3 analog, IP3-BM (10 μmol/L) was also able to increase SOCE by 31 ± 10% (n = 3, data not shown). To test whether ET-1 or IP3-BM acted by opening IP3R release channels and thereby causing a greater store depletion (and hence SOCE), we examined the effect of enhancing store depletion by increasing both the CPA concentration and the incubation time in Ca2+ free solution. When the CPA concentration was increased from 10 μmol/L to 20 μmol/L and the incubation time in Ca2+ free buffer increased from 15 min to 30 min ET-1 was no longer able to further increase SOCE (Figure 4B). Similar results were found in three other SAN preparations. These results suggest that ET-1 exerts its effects on SOCE via activation of IP3Rs and caused Ca2+ release and store depletion rather than by direct stimulation of SOC channels.


The involvement of TRPC3 channels in sinoatrial arrhythmias.

Ju YK, Lee BH, Trajanovska S, Hao G, Allen DG, Lei M, Cannell MB - Front Physiol (2015)

Modulation of store-operated Ca entry (SOCE) by ET-1 and 2-APB. SOCE was induced by using cyclopiazonic acid (CPA) and low external Ca2+. The addition timing of extracellular Ca2+ change is indicated in the top panels. (A) The effect of ET-1 on SOCE induced by 10 μM CPA with 15 min incubation in Ca2+ free Tyrode's solution. (B) The effect of ET-1 on SOCE induced by 20 μM CPA with 30 min incubation in Ca2+ free Tyrode's solution. (C) The effect of 40 μM 2-APB on SOCE. 2-APB was added in the same time of reintroduction of extracellular Ca2+ after perfusion of Ca2+ free Tyrode's Solution containing 10 μM CPA. (D) The effect of 40 μM 2-APB on SOCE. 2-APB was added into the Ca2+ free Tyrode's solution with 10 μM CPA during the 15 min incubation period. The gray traces represent controls; the black traces represent the treatments with ET-1 (A,B) or 2-APB (C,D), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373262&req=5

Figure 4: Modulation of store-operated Ca entry (SOCE) by ET-1 and 2-APB. SOCE was induced by using cyclopiazonic acid (CPA) and low external Ca2+. The addition timing of extracellular Ca2+ change is indicated in the top panels. (A) The effect of ET-1 on SOCE induced by 10 μM CPA with 15 min incubation in Ca2+ free Tyrode's solution. (B) The effect of ET-1 on SOCE induced by 20 μM CPA with 30 min incubation in Ca2+ free Tyrode's solution. (C) The effect of 40 μM 2-APB on SOCE. 2-APB was added in the same time of reintroduction of extracellular Ca2+ after perfusion of Ca2+ free Tyrode's Solution containing 10 μM CPA. (D) The effect of 40 μM 2-APB on SOCE. 2-APB was added into the Ca2+ free Tyrode's solution with 10 μM CPA during the 15 min incubation period. The gray traces represent controls; the black traces represent the treatments with ET-1 (A,B) or 2-APB (C,D), respectively.
Mentions: After initial incubation of the SAN in Ca2+ free Tyrode's with the SR uptake blocked with CPA (10 μmol/L), reintroduction of Ca2+ (1.8 mmol/L) caused a significant Ca2+ influx (i.e., SOCE) as shown by an increase in Indo-1 ratio (Figure 4A). Importantly, peak SOCE was increased by 63 ± 10% (n = 4, P < 0.05) in the presence of ET-1, a representative trace of which is shown in Figure 4A. Addition of the membrane permeant IP3 analog, IP3-BM (10 μmol/L) was also able to increase SOCE by 31 ± 10% (n = 3, data not shown). To test whether ET-1 or IP3-BM acted by opening IP3R release channels and thereby causing a greater store depletion (and hence SOCE), we examined the effect of enhancing store depletion by increasing both the CPA concentration and the incubation time in Ca2+ free solution. When the CPA concentration was increased from 10 μmol/L to 20 μmol/L and the incubation time in Ca2+ free buffer increased from 15 min to 30 min ET-1 was no longer able to further increase SOCE (Figure 4B). Similar results were found in three other SAN preparations. These results suggest that ET-1 exerts its effects on SOCE via activation of IP3Rs and caused Ca2+ release and store depletion rather than by direct stimulation of SOC channels.

Bottom Line: We will then present some of our recent research progress in this field.Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3(-/-) mice) compared to wild type controls.We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Medical Sciences, Bosch Institute, University of Sydney Sydney, NSW, Australia.

ABSTRACT
Atrial fibrillation (AF) is a significant contributor to cardiovascular morbidity and mortality. The currently available treatments are limited and AF continues to be a major clinical challenge. Clinical studies have shown that AF is frequently associated with dysfunction in the sino-atrial node (SAN). The association between AF and SAN dysfunction is probably related to the communication between the SAN and the surrounding atrial cells that form the SAN-atrial pacemaker complex and/or pathological processes that affect both the SAN and atrial simultaneously. Recent evidence suggests that Ca(2+) entry through TRPC3 (Transient Receptor Potential Canonical-3) channels may underlie several pathophysiological conditions -including cardiac arrhythmias. However, it is still not known if atrial and sinoatrial node cells are also involved. In this article we will first briefly review TRPC3 and IP3R signaling that relate to store/receptor-operated Ca(2+) entry (SOCE/ROCE) mechanisms and cardiac arrhythmias. We will then present some of our recent research progress in this field. Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3(-/-) mice) compared to wild type controls. We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R. Activation of G-protein coupled receptors (GPCRs) signaling that is able to modulate SOCE/ROCE and Ang II induced Ca(2+) homeostasis changes in sinoatrial complex being linked to TRPC3. The results provide new evidence that TRPC3 may play a role in sinoatrial and atrial arrhythmias that are caused by GPCRs activation.

No MeSH data available.


Related in: MedlinePlus