TY - JOUR
T1 - What keeps us ticking
T2 - a funny current, a calcium clock, or both?
AU - Lakatta, Edward G.
AU - DiFrancesco, Dario
N1 - Funding Information:
Dr. DiFrancesco wishes to thank Drs. M. Baruscotti, A. Bucchi and A. Barbuti for reading the manuscript. During this work Dr. DiFrancesco was supported by grants from the EU (Normacor) and the Ministero dell'Istruzione, dell'Università e della Ricerca (Laboratorio FIRB di Scienze Cardiovascolari and PRIN 2006).
Funding Information:
Dr. Lakatta thanks Drs. Victor Maltsev and Tatiana Vinogradova for their thoughtful reading of the manuscript. Dr. Lakatta's work is supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.
PY - 2009/8
Y1 - 2009/8
N2 - On the basis of prolific experimental evidence supported by novel numerical modeling, it is reasonable to conclude that the tightly coupled system of SR Ca2+ cycling and surface membrane proteins is the clock that controls SANC normal automaticity, leading to their mutual functional entrainment [115]. The clock is robust because the same factors that regulate SR Ca2+ cycling, i.e., Ca2+ and PKA and CaMKII-dependent protein phosphorylation, also regulate sarcolemmal ion channel function and thereby couple SR Ca2+ cycling to the surface membrane. G protein-coupled receptor signaling ensures pacemaker flexibility by affecting rate regulation by impacting on the very same factors that ensure pacemaker fail-safe operation or robustness in a given steady state. Intimately intertwined robustness and flexibility of the heart's pacemaker ensure a wide range of stable heart rates. Rebuttal: DiFrancesco. Ed, you concentrate on the existence of a complex cellular machinery underlying Ca2+ cycling. I have no problem with this, but we are discussing here the function of Ca2+ cycling and that of the funny current. Clearly, none of the mechanisms working in a pacemaker cell can be functionally removed without major impact on the whole behaviour of the cell. Normal physiological pacemaking depends on the integrity of all participating cellular processes, and pointing out that one mechanism is essential for rate control does not mean that mechanism is responsible for that control. The questions we need to address here are simpler ones: which is the physiological process selected to generate spontaneous activity (or, better, discriminating between pacing and silent cardiomyocytes)? Also, when a change in rate is required, which is the physiological process selected, typically by the autonomic nervous system, to produce it? A change in the rate of Ca2+ fluctuations, or a change in If?
AB - On the basis of prolific experimental evidence supported by novel numerical modeling, it is reasonable to conclude that the tightly coupled system of SR Ca2+ cycling and surface membrane proteins is the clock that controls SANC normal automaticity, leading to their mutual functional entrainment [115]. The clock is robust because the same factors that regulate SR Ca2+ cycling, i.e., Ca2+ and PKA and CaMKII-dependent protein phosphorylation, also regulate sarcolemmal ion channel function and thereby couple SR Ca2+ cycling to the surface membrane. G protein-coupled receptor signaling ensures pacemaker flexibility by affecting rate regulation by impacting on the very same factors that ensure pacemaker fail-safe operation or robustness in a given steady state. Intimately intertwined robustness and flexibility of the heart's pacemaker ensure a wide range of stable heart rates. Rebuttal: DiFrancesco. Ed, you concentrate on the existence of a complex cellular machinery underlying Ca2+ cycling. I have no problem with this, but we are discussing here the function of Ca2+ cycling and that of the funny current. Clearly, none of the mechanisms working in a pacemaker cell can be functionally removed without major impact on the whole behaviour of the cell. Normal physiological pacemaking depends on the integrity of all participating cellular processes, and pointing out that one mechanism is essential for rate control does not mean that mechanism is responsible for that control. The questions we need to address here are simpler ones: which is the physiological process selected to generate spontaneous activity (or, better, discriminating between pacing and silent cardiomyocytes)? Also, when a change in rate is required, which is the physiological process selected, typically by the autonomic nervous system, to produce it? A change in the rate of Ca2+ fluctuations, or a change in If?
KW - Ca cycling
KW - HCN channels
KW - HCN4 channelopathies
KW - I current
KW - I, I, I
KW - SERCA-2 Ryanodine receptors
KW - biological pacemaker
KW - cAMP
KW - cardiac pacemaker cells
KW - diastolic depolarization
KW - funny channels
KW - heart rate
KW - ion channels
KW - ivabradine
KW - pacemaker
KW - phospholamban
KW - protein kinase A-depdendent phosphorylation
KW - sinus bradycardia
KW - β-adrenergic receptor stimulation
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UR - http://www.scopus.com/inward/citedby.url?scp=67649104033&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2009.03.022
DO - 10.1016/j.yjmcc.2009.03.022
M3 - Comment/debate
C2 - 19361514
AN - SCOPUS:67649104033
SN - 0022-2828
VL - 47
SP - 157
EP - 170
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -