Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K1.1, in Sinus Node Function and Arrhythmia Risk.

Background: encodes the α-subunit of the large-conductance Ca-activated K channel, K1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K1.

The involvement of TRPC3 channels in sinoatrial arrhythmias.

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).

Store-operated calcium entry and the localization of STIM1 and Orai1 proteins in isolated mouse sinoatrial node cells.

In many non-excitable and excitable cells, store-operated calcium entry (SOCE) represents an additional pathway for calcium entry upon Ca(2+) store depletion. In a previous study, we demonstrated SOCE activity in intact mouse cardiac pacemaker tissue, specifically from sinoatrial node (SAN) tissue. However, store content as a key determinant of SOCE activity is difficult to measure in intact SAN tissue.

Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms.

Intracellular Ca(2+) plays an important role in the control of the heart rate through the interaction between Ca(2+) release by ryanodine receptors in the sarcoplasmic reticulum (SR) and the extrusion of Ca(2+) by the sodium-calcium exchanger which generates an inward current. A second type of SR Ca(2+) release channel, the inositol 1,4,5-trisphosphate receptor (IP(3)R), can release Ca(2+) from SR stores in many cell types, including cardiac myocytes. However, it is still uncertain whether IP(3)Rs play any functional role in regulating the heart rate.

Distribution and functional role of inositol 1,4,5-trisphosphate receptors in mouse sinoatrial node.

Rationale: Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) have been implicated in the generation of arrhythmias and cardiac muscle nuclear signaling. However, in the mammalian sinoatrial node (SAN), where the heart beat originates, the expression and functional activity of IP(3)Rs have not been investigated.

Objectives: To determine whether SAN express IP(3)Rs and which isoforms are present.

Phosphoinositide signalling and cardiac arrhythmias.

Arrhythmias arise from a complex interaction between structural changes in the myocardium and changes in cellular electrophysiology. Electrophysiological balance requires precise control of sarcolemmal ion channels and exchangers, many of which are regulated by phospholipid, phosphatidylinositol(4,5)bisphosphate. Phosphatidylinositol(4,5)bisphosphate is the immediate precursor of inositol(1,4,5)trisphosphate, a regulator of intracellular Ca2+ signalling and, therefore, a potential contributor to arrhythmogenesis by altering Ca2+ homeostasis.

Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy.

The stretch-induced increase in force production of ventricular muscle is biphasic. An abrupt increase in force coincides with the stretch, which is then followed by a slower response that develops over minutes (the slow force response or SFR). The SFR is accompanied by a slow increase in the magnitude of the intracellular Ca2+ transient, but the stretch-dependent mechanisms that give rise to this remain controversial.

Store-operated Ca2+ entry and TRPC expression; possible roles in cardiac pacemaker tissue.

Store-operated Ca(2+) channels (SOCCs) were first identified in non-excitable cells by the observation that depletion of Ca(2+) stores caused increased influx of extracellular Ca(2+). Recent studies have suggested that SOCCs might be related to the transient receptor potential (TRPC) gene family. The mechanism of cardiac pacemaking involves voltage-dependent pacemaker current; in addition there is growing evidence that intracellular sarcoplasmic reticulum (SR) Ca(2+) release plays an important role.

Store-operated Ca2+ influx and expression of TRPC genes in mouse sinoatrial node.

Store-operated Ca(2+) entry was investigated in isolated mouse sinoatrial nodes (SAN) dissected from right atria and loaded with Ca(2+) indicators. Incubation of the SAN in Ca(2+)-free solution caused a substantial decrease in resting intracellular Ca(2+) concentration ([Ca(2+)](i)) and stopped pacemaker activity. Reintroduction of Ca(2+) in the presence of cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca(2+) pump inhibitor, led to sustained elevation of [Ca(2+)](i), a characteristic of store-operated Ca(2+) channel (SOCC) activity.

The rise of [Na(+)] (i) during ischemia and reperfusion in the rat heart-underlying mechanisms.

Intracellular Na(+) concentration ([Na(+)](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na(+)](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+) overload. Part of the rise of [Na(+)](i) during ischemia may be caused by increased activity of the cardiac Na(+)/H(+) exchanger (NHE1), activated by the ischemic rise in [H(+)](i).

Cyanide inhibits the Na+/Ca2+ exchanger in isolated cardiac pacemaker cells of the cane toad.

The effects of the metabolic inhibition on the activity of the Na+/Ca2+ exchanger (NCX) were studied in single isolated pacemaker cells from the cane toad. Ca2+ influx on NCX (reverse mode) was estimated by measuring the increase in intracellular calcium concentration ([Ca2+]i) in response to extracellular Na+-free solution. After application of 2 mM sodium cyanide for 3-5 min, the peak [Ca2+]i in Na+-free solution was significantly decreased from 377+/-42 nM to 260+/-46 nM, suggesting inhibition of NCX.

ATP modulates intracellular Ca2+ and firing rate through a P2Y1 purinoceptor in cane toad pacemaker cells.

The effect of extracellular ATP (10-100 microM) on intracellular Ca2+ concentration ([Ca2+]i) and firing rate has been studied in single pacemaker cells isolated from the sinus venosus of cane toads. In spontaneously firing cells, ATP initially increased peak [Ca2+]i by 43 +/- 5 %, increased diastolic [Ca2+]i by 20 + 3 % and increased the firing rate by 58 +/- 8 %. These early effects were followed by a late phase in which both the peak [Ca2+]i and the firing rate declined.

IGF-1 enhances a store-operated Ca2+ channel in skeletal muscle myoblasts: involvement of a CD20-like protein.

Overexpression of IGF-1 in C2C12 myoblasts causes hypertrophy when myoblasts fuse to form myotubes, a response that requires elevated intracellular calcium. We show that myoblasts contain a store-operated Ca2+ channel (SOCC) whose activity is enhanced with IGF-1 overexpression. A membrane protein, CD20, can cause Ca2+ entry, which is increased by IGF-1.

Early effects of metabolic inhibition on intracellular Ca2+ in toad pacemaker cells: involvement of Ca2+ stores.

The early effects of metabolic inhibition on intracellular Ca(2+) concentration ([Ca(2+)](i)), Ca(2+) current, and sarcoplasmic reticulum (SR) Ca(2+) content were studied in single pacemaker cells from the sinus venosus of the cane toad. The amplitude of the spontaneous elevations of systolic [Ca(2+)](i) (Ca(2+) transients) was reduced after 5-min exposure to 2 mM NaCN from 338 +/- 30 to 189 +/- 37 nM (P < 0.005, n = 9), and the spontaneous firing rate was reduced from 27 +/- 2 to 12 +/- 4 beats/min (P < 0.