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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

Isolated single SAN cells express TRPC3, STIM1, and IP3R2. Confocal immunofluorenscence images of isolated single pacemaker cells. Isolated group (A) and single (B) pacemaker cells were positively stained with anti HCN4 (in green). (C) Anti-TRPC3 in red, anti-STIM1 in green. (D) Anti-IP3R2 in red, anti-STIM1 in green. (E) 3D reconstruction image using N-SIM microscopy. Anti-IP3R2 in red, anti-STIM1 in green. Areas of co-localisation appear yellow due to color mixing.
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Figure 3: Isolated single SAN cells express TRPC3, STIM1, and IP3R2. Confocal immunofluorenscence images of isolated single pacemaker cells. Isolated group (A) and single (B) pacemaker cells were positively stained with anti HCN4 (in green). (C) Anti-TRPC3 in red, anti-STIM1 in green. (D) Anti-IP3R2 in red, anti-STIM1 in green. (E) 3D reconstruction image using N-SIM microscopy. Anti-IP3R2 in red, anti-STIM1 in green. Areas of co-localisation appear yellow due to color mixing.

Mentions: Previously, we demonstrated that mouse SAN tissue expressing HCN4 mRNA also expressed TRPC3 (Ju et al., 2007). We also found that pacemaker tissue express STIM1 mRNA and protein (Liu et al., 2015). In the present study we wanted to extend these findings to the localisation of TRPC3 and STIM1 in single isolated pacemaker cells. Figure 3 shows that isolated group (Figure 3A) and single pacemaker cells (Figure 1B) were positively labeled with a HCN4 antibody (which is a common selective molecular marker for pacemaker cells). The cells isolated from same SAN region were then double labeled with TRPC3 and STIM1 antibodies, and exemplar data is shown in Figure 3C. TRPC3 (red) showed both a sarcomeric pattern as well as membrane staining while STIM1 (green) displayed both cytosolic and near membrane labeling. A previous study examined the interaction of all mammalian TRPC channels with topically expressed STIM1 and found that that the STIM1 ERM domain binds to TRPC1, TRPC4, and TRPC5 but not TRPC3, TRPC6, and TRPC7 (Worley et al., 2007). However, knock down of STIM1 significantly reduced the current carried by TRPC3 (Yuan et al., 2007). The expression of both TRPC3 and STIM1 in cardiac pacemaker cells suggested to us that TRPC3 could be involved in Ca2+ influx through SOCE.


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)

Isolated single SAN cells express TRPC3, STIM1, and IP3R2. Confocal immunofluorenscence images of isolated single pacemaker cells. Isolated group (A) and single (B) pacemaker cells were positively stained with anti HCN4 (in green). (C) Anti-TRPC3 in red, anti-STIM1 in green. (D) Anti-IP3R2 in red, anti-STIM1 in green. (E) 3D reconstruction image using N-SIM microscopy. Anti-IP3R2 in red, anti-STIM1 in green. Areas of co-localisation appear yellow due to color mixing.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Isolated single SAN cells express TRPC3, STIM1, and IP3R2. Confocal immunofluorenscence images of isolated single pacemaker cells. Isolated group (A) and single (B) pacemaker cells were positively stained with anti HCN4 (in green). (C) Anti-TRPC3 in red, anti-STIM1 in green. (D) Anti-IP3R2 in red, anti-STIM1 in green. (E) 3D reconstruction image using N-SIM microscopy. Anti-IP3R2 in red, anti-STIM1 in green. Areas of co-localisation appear yellow due to color mixing.
Mentions: Previously, we demonstrated that mouse SAN tissue expressing HCN4 mRNA also expressed TRPC3 (Ju et al., 2007). We also found that pacemaker tissue express STIM1 mRNA and protein (Liu et al., 2015). In the present study we wanted to extend these findings to the localisation of TRPC3 and STIM1 in single isolated pacemaker cells. Figure 3 shows that isolated group (Figure 3A) and single pacemaker cells (Figure 1B) were positively labeled with a HCN4 antibody (which is a common selective molecular marker for pacemaker cells). The cells isolated from same SAN region were then double labeled with TRPC3 and STIM1 antibodies, and exemplar data is shown in Figure 3C. TRPC3 (red) showed both a sarcomeric pattern as well as membrane staining while STIM1 (green) displayed both cytosolic and near membrane labeling. A previous study examined the interaction of all mammalian TRPC channels with topically expressed STIM1 and found that that the STIM1 ERM domain binds to TRPC1, TRPC4, and TRPC5 but not TRPC3, TRPC6, and TRPC7 (Worley et al., 2007). However, knock down of STIM1 significantly reduced the current carried by TRPC3 (Yuan et al., 2007). The expression of both TRPC3 and STIM1 in cardiac pacemaker cells suggested to us that TRPC3 could be involved in Ca2+ influx through SOCE.

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