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Calcium release from inositol 1,4,5-trisphosphate receptors influences cardiac pacemaker function in mouse sino-atrial node

Y.K. Ju,1 B.H. Lee,1 D. Lai,1 E.A. Woodcock,2 M.B. Cannell3 and D.G. Allen,1 1School of Medical Sciences and Bosch Institute, University of Sydney, NSW 2006, Australia, 2Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia and 3The Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

It has been found that Inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as inositol 1,4,5-trisphosphate (IP3)-gated Ca2+ channels, are expressed in working cardiac myocytes (Nosek et al., 1986). In atrial cells, accumulated evidence shows that IP3R signalling is involved in arrhythmic activity (Li et al., 2005; Woodcock, Kistler & Ju, 2009). However, there is little direct evidence whether IP3Rs expression in adult mammalian sino-atrial node (SAN), the origin site of generating rhythm in the heart. In current studies, we quantified the level of the expression of IP3Rs in the SANs by using a new cell direct qPCR technique. We find that both centre and peripheral SANs expression of IP3Rs. We also studied the effect of IP3R agonist, such as endothelin-1, IP3-butyryloxymethyl ester (IP3-BM), and antagonist 2-aminoethoxy diphenylborate (2-APB), on intracellular Ca2+ of spontaneously firing sinoatrial node preparations. In the presence of 10 nM endothelin-1, the resting [Ca2+]i was increased by 36 ± 13 % (n = 5; P < 0.05) and the firing rate was increased by 20 ± 8 % (P < 0.05). The results were similar when IP3-BM was used. IP3R antagonist 2-APB reduced intracellular Ca2+ and slowed the firing rate. However, such effects were only seen in wild type but not in IP3R2 knock out mice. The localisation of IP3R2s and IP3 induced Ca2+ sparks also further support that that IP3Rs are involved in cardiac peacemaking through the release of Ca2+ from the intracellular Ca2+ stores that are near subsarcolemmal membrane.

Li X, Zima AV, Sheikh F, Blatter LA, Chen J. (2005) Endothelin-1-induced arrhythmogenic Ca2+ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice. Circ. Res. 96: 1274-81.

Nosek TM, Williams MF, Zeigler ST, Godt RE. (1986) Inositol trisphosphate enhances calcium release in skinned cardiac and skeletal muscle. Am. J. Physiol. 250: C807-C811.

Woodcock EA, Kistler PM, Ju YK. (2009) Phosphoinositide signalling and cardiac arrhythmias. Cardiovasc. Res. 82: 286-95.