Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking

Ono, Koichi; Iwamoto, Toshihiko

doi:10.1254/jphs.fmj05002x2

Cited by 69 publications

(50 citation statements)

References 39 publications

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“…In the cardiovascular system, expression of Cav3.1 and Cav3.2 has been found in the SA and AV nodes and in arterial smooth muscle cells, where they play a role in pace-making and control of vascular tone, respectively. 37,38 Interestingly, the endogenous vasodilator nitric oxide suppresses T-type calcium currents in aterial smooth mucle cells. 39 No selective N-type or T-type small molecule blockers have been approved for clinical use.…”

Section: N-type (Cav22) and T-type (Cav3x) Channelsmentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype.

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Section: N-type (Cav22) and T-type (Cav3x) Channelsmentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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“…It is not surprising that the block of I f by Cs + had only minor effect on the pacemaker rhythm (103). It was also found that bullfrog sinus venosus cells lacked I f (104), I Ks is present in porcine SANC, I Kr is present in rat and rabbit (101), and I CaT is almost absent in porcine SANC (105). Other currents were observed only in sub-populations of SANC (I Na , I Cl ) (106) or had no obvious molecular identity (I st ) (107).…”

Section: Application Of the Membrane Current-driven Voltage Oscillatomentioning

confidence: 99%

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

2006

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Abstract. Sarcoplasmic reticulum (SR) Ca2+ cycling, that is, the Ca 2+ clock, entrained by externally delivered action potentials has been a major focus in ventricular myocyte research for the past 5 decades. In contrast, the focus of pacemaker cell research has largely been limited to membrane-delimited pacemaker mechanisms (membrane clock) driven by ion channels, as the immediate cause for excitation. Recent robust experimental evidence, based on confocal cell imaging, and supported by numerical modeling suggests a novel concept: the normal rhythmic heart beat is governed by the tight integration of both intracellular Ca 2+ and membrane clocks. In pacemaker cells the intracellular Ca 2+ clock is manifested by spontaneous, rhythmic submembrane local Ca 2+ releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca 2+ releases rhythmically activate Na + / Ca 2+ exchange inward currents that ignite action potentials, whose shape and ion fluxes are tuned by the membrane clock which, in turn, sustains operation of the intracellular Ca 2+ clock. The idea that spontaneous SR Ca 2+ releases initiate and regulate normal automaticity provides the key that reunites pacemaker and ventricular cell research, thus evolving a general theory of the initiation and strength of the heartbeat.

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“…pigs and humans), Ca 2+ may be exclusively carried via I CaL , and not I CaT ; the lack of I CaT in porcine SAN cells would be beneficial for slower pacemaker depolarization. Conversely, a high density of I CaT in mouse SAN cells would promote pacemaker depolarization, thereby increasing heart rate [20]. Importantly, since I CaT has never been detected in human heart tissue [19], clinically relevant ischemia-induced bradycardia in human SANC would not likely involve I CaT .…”

Section: Ncx and I Cat Fail During Ischemiamentioning

confidence: 99%

Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

Maltsev

Lakatta

2007

Journal of Molecular and Cellular Cardiology

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Cardiac ischemia is an important global health problem. It leads to contraction failure, arrhythmias, and cardiac cell death. Sinus bradycardia characterized by a slow heart rate (<60 bpm) is a prominent ischemia-related arrhythmia directly caused by a deficiency of heart beat initiation within the sinoatrial node (SAN), due to a failure of the heart's primary pacemaker cells (SANC). The study presented by Yi-Mei Du and Richard Nathan in this issue of Journal of Molecular and Cellular Cardiology [1] deals with the ionic basis of ischemia-induced bradycardia in isolated SANC. The results of their study not only contribute to understanding of ischemia-induced bradycardia, but also help to delineate the fundamental mechanisms of cardiac pacemaker cell function. Study design and hypothesisIn their studies, Du and Nathan simulated ischemia by superfusing SANC with a solution without glucose, at pH 6.6 that contained either 5.4 or 10 mM KCl. This lead, to a 13% or 43% reduction, respectively, in the spontaneous beating rate of freshly isolated SANC. This simulated ischemia is not true ischemia, e.g. there is no associated hypoxia or flow deficiency effects other than elevated [K + ]. Nonetheless simulated ischemia of this sort is often applied in studies like the present one. And, in their careful approach to the problem, the authors first demonstrated that their "ischemic" solutions produced bradycardia in the intact rabbit heart. Then, in isolated SANC they measured the effects of this simulated ischemia on membrane potential and ion currents under voltage clamp. Such an approach is not surprising, because it has been believed for almost half a century that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells. This dogma stems from the Nobel prize triumph of the Hodgkin-Huxley neuron membrane excitability theory [2] and subsequent modification of this theory and extrapolation to the heart cells by Noble (1960) [3]. According to this theory, generation of spontaneous action potentials (APs) by cardiac pacemaker cells is portrayed as a membrane delimited process, i.e. by a pure interplay of time-and voltage-dependent ion currents. Pacemaker field researchers have focused mainly on the identification of multiple ion current components in pacemaker cells, and their respective roles in the spontaneous diastolic depolarization of these cells (DD, Fig.1A) that brings the membrane to the excitation threshold (reviews [4,5]). Du and Nathan thus tested an hypothesis that bradycardia induced by their

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Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking

Cited by 69 publications

References 39 publications

Cardiac ion channels

Cardiac ion channels

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

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