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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

Signaling pathways involved in the activation of TRPC3. The G-protein coupled receptor (GPCRs) activates phospholiase C (PLC), resulting in generation of IP3 and diacylglycerol (DAG). IP3 activates its receptor that leads to Ca2+ release from SR/ER and the depletion of SR/ER Ca2+ store. The Ca2+ content change in the store can be sensed by STIM1, the ER Ca2+ sensor and cause store-operated Ca2+ entry (SOCE) through TRPC3 channels. An additional or alternate possibility is that DAG can directly activate TRPC3, and produce receptor-operated Ca2+ entry (ROCE). GPCRs, G-protein coupled receptors; IP3R, inositol 1,4,5-trisphosphate receptors; PLC, Phospholipase C; ROCE, Receptor–operated Ca2+ entry; SOCE, store-operated Ca2+ entry; SR/ER, sarco- endo-plasmic reticulum; STIM1, stromal interacting molecule 1; TRPC3,4,6 canonical transient receptor potential channel types 3,4,6; NCX Na/Ca exchange.
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Figure 1: Signaling pathways involved in the activation of TRPC3. The G-protein coupled receptor (GPCRs) activates phospholiase C (PLC), resulting in generation of IP3 and diacylglycerol (DAG). IP3 activates its receptor that leads to Ca2+ release from SR/ER and the depletion of SR/ER Ca2+ store. The Ca2+ content change in the store can be sensed by STIM1, the ER Ca2+ sensor and cause store-operated Ca2+ entry (SOCE) through TRPC3 channels. An additional or alternate possibility is that DAG can directly activate TRPC3, and produce receptor-operated Ca2+ entry (ROCE). GPCRs, G-protein coupled receptors; IP3R, inositol 1,4,5-trisphosphate receptors; PLC, Phospholipase C; ROCE, Receptor–operated Ca2+ entry; SOCE, store-operated Ca2+ entry; SR/ER, sarco- endo-plasmic reticulum; STIM1, stromal interacting molecule 1; TRPC3,4,6 canonical transient receptor potential channel types 3,4,6; NCX Na/Ca exchange.

Mentions: The most prominent Ca2+-dependent ionic current during pacemaker activity is the Na/Ca exchange (NCX) current which not only contributes to pacemaker current(s) but may also produce arrhythmogenic electrical activity (Sipido et al., 2006) which is related to abnormalities in Ca2+ handling leading to abnormal NCX currents (Hove-Madsen et al., 2004; Vest et al., 2005). Spontaneous Ca2+ release events or “leak” via the ryanodine receptor (RyR), the major cardiac SR Ca2+ release channel, will produce depolarizing NCX current and contribute spontaneous membrane depolarization(s) to feed the genesis of AF (for review see Greiser et al., 2011; Wakili et al., 2011). In addition, AF has also been linked to Ca2+ release via a second class of SR Ca2+ release channel, inositol 1,4,5-trisphosphate receptor family (IP3Rs) (Woodcock et al., 2000; Mackenzie et al., 2002; Li et al., 2005; Berridge, 2009). Activation of IP3Rs by IP3 is linked to the activation of G-protein coupled receptors (GPCRs) and the phospholipase C (PLC)-IP3 signaling pathway (see Figure 1). Activation of GPCRs by agonists such as angiotensin II (Ang II) or endothelin-1 (ET-1) can cause SAN dysfunction (Neef et al., 2010) and AF (Woodcock et al., 2000; Mackenzie et al., 2002; Li et al., 2005).


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)

Signaling pathways involved in the activation of TRPC3. The G-protein coupled receptor (GPCRs) activates phospholiase C (PLC), resulting in generation of IP3 and diacylglycerol (DAG). IP3 activates its receptor that leads to Ca2+ release from SR/ER and the depletion of SR/ER Ca2+ store. The Ca2+ content change in the store can be sensed by STIM1, the ER Ca2+ sensor and cause store-operated Ca2+ entry (SOCE) through TRPC3 channels. An additional or alternate possibility is that DAG can directly activate TRPC3, and produce receptor-operated Ca2+ entry (ROCE). GPCRs, G-protein coupled receptors; IP3R, inositol 1,4,5-trisphosphate receptors; PLC, Phospholipase C; ROCE, Receptor–operated Ca2+ entry; SOCE, store-operated Ca2+ entry; SR/ER, sarco- endo-plasmic reticulum; STIM1, stromal interacting molecule 1; TRPC3,4,6 canonical transient receptor potential channel types 3,4,6; NCX Na/Ca exchange.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Signaling pathways involved in the activation of TRPC3. The G-protein coupled receptor (GPCRs) activates phospholiase C (PLC), resulting in generation of IP3 and diacylglycerol (DAG). IP3 activates its receptor that leads to Ca2+ release from SR/ER and the depletion of SR/ER Ca2+ store. The Ca2+ content change in the store can be sensed by STIM1, the ER Ca2+ sensor and cause store-operated Ca2+ entry (SOCE) through TRPC3 channels. An additional or alternate possibility is that DAG can directly activate TRPC3, and produce receptor-operated Ca2+ entry (ROCE). GPCRs, G-protein coupled receptors; IP3R, inositol 1,4,5-trisphosphate receptors; PLC, Phospholipase C; ROCE, Receptor–operated Ca2+ entry; SOCE, store-operated Ca2+ entry; SR/ER, sarco- endo-plasmic reticulum; STIM1, stromal interacting molecule 1; TRPC3,4,6 canonical transient receptor potential channel types 3,4,6; NCX Na/Ca exchange.
Mentions: The most prominent Ca2+-dependent ionic current during pacemaker activity is the Na/Ca exchange (NCX) current which not only contributes to pacemaker current(s) but may also produce arrhythmogenic electrical activity (Sipido et al., 2006) which is related to abnormalities in Ca2+ handling leading to abnormal NCX currents (Hove-Madsen et al., 2004; Vest et al., 2005). Spontaneous Ca2+ release events or “leak” via the ryanodine receptor (RyR), the major cardiac SR Ca2+ release channel, will produce depolarizing NCX current and contribute spontaneous membrane depolarization(s) to feed the genesis of AF (for review see Greiser et al., 2011; Wakili et al., 2011). In addition, AF has also been linked to Ca2+ release via a second class of SR Ca2+ release channel, inositol 1,4,5-trisphosphate receptor family (IP3Rs) (Woodcock et al., 2000; Mackenzie et al., 2002; Li et al., 2005; Berridge, 2009). Activation of IP3Rs by IP3 is linked to the activation of G-protein coupled receptors (GPCRs) and the phospholipase C (PLC)-IP3 signaling pathway (see Figure 1). Activation of GPCRs by agonists such as angiotensin II (Ang II) or endothelin-1 (ET-1) can cause SAN dysfunction (Neef et al., 2010) and AF (Woodcock et al., 2000; Mackenzie et al., 2002; Li et al., 2005).

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