Sodium-Calcium Exchange in Excitable Cells: Fuzzy Space

Lederer, W. J.; Niggli, Ernst; Hadley, R. W.

doi:10.1126/science.2326638

Cited by 288 publications

(178 citation statements)

References 21 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…Because the Na + current activates and inactivates rapidly during the upstroke of the action potential, only a small change in Na i + is effected by this mechanism (8-25 μM per beat [1,11]), though Na + current may significantly contribute to an increase in Na i + during rapid stimulation [12].…”

Section: Relationship Between Na I + and Ca 2+ Handling Physiologymentioning

confidence: 99%

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

O’Rourke

Maack

2007

Drug Discovery Today: Disease Models

View full text Add to dashboard Cite

Ca 2+ is well known as the central player in cardiac cell physiology, mediating Ca 2+ activation of myosin ATPase and contraction, the stimulation of Ca 2+ -activated signaling pathways and modulation of mitochondrial energy production. Abnormalities of Ca 2+ handling are a well-studied mechanism of decompensation in heart failure. Less appreciated is the role of cytosolic Na + (Na i + ), which can dramatically influence the transfer rates and distribution of Ca 2+ among the intracellular compartments of the myocyte. Since Na i + can vary widely under different physiological and pathological conditions, and its effects depend on multiple ion gradients and membrane electrical potentials, unraveling the global influence of Na i + on cell function is complex, requiring an integrative view of cardiomyocyte physiology. Here, we discuss how abnormal Na i + regulation not only influences the cytosolic Ca 2+ transient and the cellular action potential but also alters mitochondrial Ca 2+ uptake and the balance of energy supply and demand of the cardiomyocyte, which may contribute to oxidative stress and cardiac decompensation. The implications for sudden cardiac death and the potential for novel therapeutic interventions are discussed. Na i + balance: the playersNa i + balance in the heart cell is maintained by a variety of ion channels, pumps and exchangers whose function is strongly influenced by the transmembrane gradients of various ions, and in some cases, by the electrical potential across the sarcolemmal or organelle membranes ( Fig. 1; see [1] for a review). At the sarcolemma, two well-known processes contribute to unidirectional Na + fluxes during the cardiac cycle; voltage-dependent Na + channels mediate the rapid inward Na + current (I Na ) during the upstroke of the cellular action potential and may also contribute to persistent Na + influx, while the Na + /K + ATPase (NKA) utilizes the energy released by ATP hydrolysis to pump Na + out of the cell against a concentration gradient in exchange for K + in an electrogenic process (3Na + :2K + ). A variety of electroneutral exchangers also influence Na i + when ion homeostasis is disturbed under pathological conditions; these include the Na + /H + exchanger (NHE), the Na + /HCO 3 -cotransporter (NBC), the Na + /K + / 2Cl -cotransporter (NKCC) and the Na + /Mg 2+ exchanger (NMgX). Influx of Na + through these pathways is generally well compensated by NKA action. Uniquely, under physiological conditions, the sarcolemmal Na + /Ca 2+ exchanger (NCX) operates in both the forward-mode (Ca 2+ extrusion/Na + entry) and reverse-mode (Ca 2+ entry/Na + extrusion) during different phases of the cardiac cycle, depending on the dynamically changing membrane potential and gradients of Na + and Ca 2+ across the sarcolemma. Its sensitivity to membrane voltage is

show abstract

Section: Relationship Between Na I + and Ca 2+ Handling Physiologymentioning

confidence: 99%

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

O’Rourke

Maack

2007

Drug Discovery Today: Disease Models

View full text Add to dashboard Cite

show abstract

“…This indicates that the bulk cytosolic nucleotide composition cannot be the sole determinant of K ATP channel function. Rather, K ATP channels could sense local nucleotide concentrations set by ATPases in the submembrane space at a level distinct from that of the "bulk" cytosol [52,54,86], provided that significant diffusional limitations within the cell exist to establish distinct cellular compartments [15,[87][88][89]. However, such cellular compartmentalization would obstruct proper energetic sensing by K ATP channels, as channel gating would be distorted by local fluctuations of nucleotides, remaining weakly dependent on the cellular metabolic status.…”

Section: The K Atp Channel Complex As a Component Of The Cellular Enementioning

confidence: 99%

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

Alekseev

Hodgson

Karger

et al. 2005

Journal of Molecular and Cellular Cardiology

108

View full text Add to dashboard Cite

Cardiac ATP-sensitive K + (K ATP ) channels, gated by cellular metabolism, are formed by association of the inwardly rectifying potassium channel Kir6.2, the potassium conducting subunit, and SUR2A, the ATP-binding cassette protein that serves as the regulatory subunit. Kir6.2 is the principal site of ATP-induced channel inhibition, while SUR2A regulates K + flux through adenine nucleotide binding and catalysis. The ATPase-driven conformations within the regulatory SUR2A subunit of the K ATP channel complex have determinate linkage with the states of the channel's pore. The probability and life-time of ATPase-induced SUR2A intermediates, rather than competitive nucleotide binding alone, defines nucleotide-dependent K ATP channel gating. Cooperative interaction, instead of independent contribution of individual nucleotide binding domains within the SUR2A subunit, serves a decisive role in defining K ATP channel behavior. Integration of K ATP channels with the cellular energetic network renders these channel/enzyme heteromultimers high-fidelity metabolic sensors. This vital function is facilitated through phosphotransfer enzyme-mediated transmission of controllable energetic signals. By virtue of coupling with cellular energetic networks and the ability to decode metabolic signals, K ATP channels set membrane excitability to match demand for homeostatic maintenance. This new paradigm in the operation of an ion channel multimer is essential in providing the basis for K ATP channel function in the cardiac cell, and for understanding genetic defects associated with life-threatening diseases that result from the inability of the channel complex to optimally fulfill its physiological role.

show abstract

“…3A). Provided that nucleotide mobility between cytosolic and submembrane compartments is limited [31], these submembrane nucleotide levels could be generated by membrane ATPases [30,39] including ATP hydrolysis by the K ATP channel [22,24], as well as AK (ATP + AMP ↔ 2 ADP; Fig. 3A).…”

Section: K Atp Channel Gating and Ak-catalyzed Nucleotide Conversion mentioning

confidence: 99%

“…Rather, K ATP channels could sense local nucleotides set by ATPases in the submembrane space at a level distinct from that of the `bulk' cytosol [25,29,30], provided there exist significant diffusional limitations between the two cellular compartments. Yet, compartmentalization [9,31] would hamper recognition of energetic signals by K ATP channels, as channel gating would be relegated to local fluctuations of nucleotides. Therefore, in a compartmentalized cell, adequate K ATP channel regulation requires transmission of energetic signals across diffusional barriers, and translation into a local nucleotide change sufficient for channel activation.…”

mentioning

confidence: 99%

Nucleotide-gated K_ATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

et al. 2004

View full text Add to dashboard Cite

Transmission of energetic signals to membrane sensors, such as the ATP-sensitive K + (K ATP ) channel, is vital for cellular adaptation to stress. Yet, cell compartmentation implies diffusional hindrances that hamper direct reception of cytosolic energetic signals. With high intracellular ATP levels, K ATP channels may sense not bulk cytosolic, but rather local submembrane nucleotide concentrations set by membrane ATPases and phosphotransfer enzymes. Here, we analyzed the role of adenylate kinase and creatine kinase phosphotransfer reactions in energetic signal transmission over the strong diffusional barrier in the submembrane compartment, and translation of such signals into a nucleotide response detectable by K ATP channels. Facilitated diffusion provided by creatine kinase and adenylate kinase phosphotransfer dissipated nucleotide gradients imposed by membrane ATPases, and shunted diffusional restrictions. Energetic signals, simulated as deviation of bulk ATP from its basal level, were amplified into an augmented nucleotide response in the submembrane space due to failure under stress of creatine kinase to facilitate nucleotide diffusion. Tuning of creatine kinase-dependent amplification of the nucleotide response was provided by adenylate kinase capable of adjusting the ATP/ADP ratio in the submembrane compartment securing adequate K ATP channel response in accord with cellular metabolic demand. Thus, complementation between creatine kinase and adenylate kinase systems, here predicted by modeling and further supported experimentally, provides a mechanistic basis for metabolic sensor function governed by alterations in intracellular phosphotransfer fluxes. KeywordsATP-sensitive K + channel; nucleotide diffusion; metabolic sensor; intracellular compartment; heart Metabolic sensing by K ATP channelsMaintenance of homeostasis requires efficient transmission of energetic signals from sites of ATP generation to ATP sensors governing cellular response [1][2][3][4][5][6]. In the compartmentalized cell environment, energetic signaling must integrate detection, amplification and delivery of metabolic signals arising from deviations in adenine nucleotide levels [1][2][3][4][5][6][7][8][9]. While the identity of energy-responsive elements is being increasingly resolved, the molecular mechanisms that synchronize metabolic sensor function with cell metabolism remain largely unknown. © 2004 Kluwer Academic PublishersAddress for offprints: A.E. Alekseev, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Guggenheim 7, Rochester, MN 55905, USA (E-mail: alekseev.alexey@mayo.edu). (Fig. 1A) [18][19][20]. The sensor role of cardiac K ATP channels stems from the nonequivalent properties of nucleotide binding domains (NBD1 and NBD2) in the SUR2A subunit (Fig. 1A). NBD1 binds nucleotides whereas NBD2 hydrolyzes ATP, with NBDs working in tandem to gate K ATP channels [21][22][23]. The ATP hydrolysis cycle at SUR2A drives conformational transitio...

show abstract

Sodium-Calcium Exchange in Excitable Cells: Fuzzy Space

Cited by 288 publications

References 21 publications

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

Nucleotide-gated K_ATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

Contact Info

Product

Resources

About

Sodium-Calcium Exchange in Excitable Cells: Fuzzy Space

Cited by 288 publications

References 21 publications

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

Nucleotide-gated KATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

Contact Info

Product

Resources

About

Nucleotide-gated K_ATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment