Modulation of the hyperpolarization-activated current (If) by calcium and calmodulin in the guinea-pig sino-atrial node

Rigg, Lauren; Mattick, Paul A. D.; Heath, Bronagh; Terrar, Derek A.

doi:10.1016/s0008-6363(02)00668-5

Cited by 51 publications

(59 citation statements)

References 28 publications

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“…Indeed, the loss of I h might be considered a compensatory measure in the context of injury. While the present experiments do not indicate a mechanism by which I h in decreased after axotomy, it is possible that axotomy-induced depression of both resting levels of cytosolic Ca 2+ as well as the transient rises of Ca 2+ that accompany neuronal activation (Fuchs et al, 2005;Fuchs et al, 2007) may result in lowered activity of Ca 2+ /calmodulindependent protein kinase II, which is a regulator of I h activity (Fan et al, 2005;Rigg et al, 2003).…”

Section: Discussioncontrasting

confidence: 71%

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Hogan

Poroli

2008

Brain Research

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In various excitable tissues, the hyperpolarization-activated, cyclic nucleotide-gated current (I h ) contributes to burst firing by depolarizing the membrane after a period of hyperpolarization. Alternatively, conductance through open channels I h channels of the resting membrane may impede excitability. Since primary sensory neurons of the dorsal root ganglion show both loss of I h and elevated excitability after peripheral axonal injury, we examined the contribution of I h to excitability of these neurons. We used a sharp electrode intracellular technique to record from neurons in nondissociated ganglia to avoid potential artefacts due to tissue dissociation and cytosolic dialysis. Neurons were categorized by conduction velocity. I h induced by hyperpolarizing voltage steps was completely blocked by ZD7288 (approximately 10μM), which concurrently eliminated the depolarizing sag of transmembrane potential during hyperpolarizing current injection. I h was most prominent in rapidly conducting Aα/β neurons, in which ZD7288 produced resting membrane hyperpolarization, slowed conduction velocity, prolonged action potential (AP) duration, and elevated input resistance. The rheobase current necessary to trigger an AP was elevated and repetitive firing was inhibited by ZD7288, indicating an excitatory influence of I h . Less I h was evident in more slowly conducting Aδ neurons, resulting in diminished effects of ZD7288 on AP parameters. Repetitive firing in these neurons was also inhibited by ZD7288, and the peak frequency of AP transmission during tetanic bursts was diminished by ZD7288. Slowly conducting C-type neurons showed minimal I h , and no effect of ZD7288 on excitability was seen. After spinal nerve ligation, axotomized neurons had less I h compared to control neurons and showed minimal effects of ZD7288 application. We conclude that I h supports sensory neuron excitability, and loss of I h is not a factor contributing to increased neuronal excitability after peripheral axonal injury.

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Section: Discussioncontrasting

confidence: 71%

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Hogan

Poroli

2008

Brain Research

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“…Of course, other currents are known to contribute to the pacemaker depolarization, and some of these may be regulated by cytosolic [Ca 2+ ], including I f and delayed rectifier K + currents (Tohse, 1990;Rigg et al 2003). However, inhibition of many of the 'established' pacemaking currents is associated only with a slowing of beating rate in guinea-pig SA node cells, rather than a cessation.…”

Section: Discussionmentioning

confidence: 99%

Fundamental importance of Na⁺–Ca²⁺ exchange for the pacemaking mechanism in guinea‐pig sino‐atrial node

Sanders¹,

Rakovic²,

Lowe³

et al. 2006

The Journal of Physiology

107

120

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Na + -Ca 2+ exchange (NCX) current has been suggested to play a role in cardiac pacemaking, particularly in association with Ca 2+ release from the sarcoplasmic reticulum (SR) that occurs just before the action potential upstroke. The present experiments explore in more detail the contribution of NCX to pacemaking. Na + -Ca 2+ exchange current was inhibited by rapid switch to low-Na + solution (with Li + replacing Na + ) within the time course of a single cardiac cycle to avoid slow secondary effects. Rapid switch to low-Na + solution caused immediate cessation of spontaneous action potentials. ZD7288 (3 μM), to block I f (funny current) channels, slowed but did not stop the spontaneous activity, and tetrodotoxin (10 μM), to block Na + channels, had little effect, but in the presence of either of these agents, rapid switch to low-Na + solution again caused immediate cessation of spontaneous action potentials. Spontaneous electrical activity was also stopped following loading of the cells with the Ca 2+ chelators BAPTA and EGTA, and by exposure to the NCX inhibitor KB-R7943 (5 μM). When rapid switch to low-Na + solution caused cessation of spontaneous activity, this was found (using confocal microscopy, with fluo-4 as the

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“…47 Calcium signaling is a critical component of the excitation-contraction coupling necessary for cardiac activity. 48 Moreover, alterations in intracellular calcium may influence sinoatrial pacemaking through hyperpolarization-activated current, 49 and calcineurin contributes to calcium homeostasis by modulating the ATPase activity of Ca2 ϩ pumps. 50 Given the role of MYOZ2 in the regulation of calcineurin activation, it may indirectly influence calcium signaling and pacemaker function.…”

Section: Discussionmentioning

confidence: 99%

Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4

et al. 2004

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Abstract-Multiple studies have identified resting heart rate as a risk factor for cardiovascular disease independent of other cardiovascular disease risk factors (such as dyslipidemia and hypertension). Previous studies have examined heart rate in hypertensive individuals, but little is known about the genetic determination of resting heart rate in a normal population. Therefore, our objective was to perform a genome screen on a population containing normotensive and hypertensive individuals. We performed variance decomposition linkage analysis using maximum likelihood methods at Ϸ10 cM intervals in 2209 individuals of predominantly North European ancestry. We estimated the heritability of resting heart rate to be 26% and obtained significant evidence of linkage (logarithm of the odds [LOD]ϭ3.9) for resting heart rate on chromosome 4q. This signal is in the same region as a quantitative trait locus (QTL) for long QT syndrome 4 and a QTL for heart rate in rats. However, resting heart rate is often overlooked as a risk factor, even though multiple studies have identified resting heart rate as a CVD risk factor. [3][4][5][6][7][8][9][10][11] Moreover, although associated with other CVD risk factors, resting heart rate is an independent predictor of CVD. 3,6,12 Given the potential clinical significance of resting heart rate, mechanisms of heart rate control are of great biomedical interest. In brief, a heartbeat begins with a small group of specialized muscle cells in the sinoatrial node. These cells generate electrical signals that spread throughout the heart and cause it to contract with a regular, steady beat. Although the sinoatrial node generates the heartbeat, heart rate is under tight neurohumoral control.Interestingly, genetic factors also influence heart rate. Heart rate has been demonstrated to have a significant genetic component of variation. 13 Additionally, quantitative trait locus or loci (QTL) for heart rate have been identified in drosophila, 14 mice, 15 rats, 16 -18 and humans. 19 However, most genetic studies have used hypertensive subjects. Given that heart rate is associated with blood pressure, 4,8,10 it is unclear whether the QTL are applicable to the normal variation in heart rate or are specific to elevated blood pressure. Therefore, our objective was to perform a genome screen on a population not ascertained on hypertensive status. Furthermore, because heart rate has been associated with CVD risk factors, we will examine the relationship between heart rate and CVD risk factors in a subset of unrelated individuals. Methods SubjectsSubjects were participants of the Metabolic Risk Complications of Obesity Genes project, which recruited participants and their families from Take Off Pounds Sensibly, Inc (TOPS) membership in the midwestern United States. 20 Research protocols were approved by the Institutional Review Board of the Medical College of Wisconsin.In this study, 2209 individuals distributed across 411 white families of predominantly northern European ancestry participated. Exclusion c...

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Modulation of the hyperpolarization-activated current (If) by calcium and calmodulin in the guinea-pig sino-atrial node

Cited by 51 publications

References 28 publications

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Fundamental importance of Na⁺–Ca²⁺ exchange for the pacemaking mechanism in guinea‐pig sino‐atrial node

Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4

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Modulation of the hyperpolarization-activated current (If) by calcium and calmodulin in the guinea-pig sino-atrial node

Cited by 51 publications

References 28 publications

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Fundamental importance of Na+–Ca2+ exchange for the pacemaking mechanism in guinea‐pig sino‐atrial node

Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4

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Fundamental importance of Na⁺–Ca²⁺ exchange for the pacemaking mechanism in guinea‐pig sino‐atrial node