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Diana L Kunze - One of the best experts on this subject based on the ideXlab platform.

  • kcnq m currents contribute to the resting membrane potential in rat visceral sensory neurons
    The Journal of Physiology, 2006
    Co-Authors: Cynthia L. Wladyka, Diana L Kunze
    Abstract:

    The M-current is a slowly activating, non-inactivating potassium current that has been shown to be present in numerous cell types. In this study, KCNQ2, Q3 and Q5, the molecular correlates of M-current in neurons, were identified in the visceral sensory neurons of the nodose ganglia from rats through immunocytochemical studies. All neurons showed expression of each of the three proteins. In voltage clamp studies, the cognition-enhancing drug linopirdine (1-50 microM) and its analogue, XE991 (10 microM), quickly and irreversibly blocked a small, slowly activating current that had kinetic properties similar to KCNQ/M-currents. This current activated between -60 and -55 mV, had a voltage-dependent activation Time Constant of 208 +/- 12 ms at -20 mV, a Deactivation Time Constant of 165 +/- 24 ms at -50 mV and V1/2 of -24 +/- 2 mV, values which are consistent with previous reports for endogenous M-currents. In current clamp studies, these drugs also led to a depolarization of the resting membrane potential at values as negative as -60 mV. Flupirtine (10-20 microM), an M-current activator, caused a 3-14 mV leftward shift in the current-voltage relationship and also led to a hyperpolarization of resting membrane potential. These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages.

  • KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons.
    The Journal of Physiology, 2006
    Co-Authors: Cynthia L. Wladyka, Diana L Kunze
    Abstract:

    The M-current is a slowly activating, non-inactivating potassium current that has been shown to be present in numerous cell types. In this study, KCNQ2, Q3 and Q5, the molecular correlates of M-current in neurons, were identified in the visceral sensory neurons of the nodose ganglia from rats through immunocytochemical studies. All neurons showed expression of each of the three proteins. In voltage clamp studies, the cognition-enhancing drug linopirdine (1–50 μm) and its analogue, XE991 (10 μm), quickly and irreversibly blocked a small, slowly activating current that had kinetic properties similar to KCNQ/M-currents. This current activated between −60 and −55 mV, had a voltage-dependent activation Time Constant of 208 ± 12 ms at −20 mV, a Deactivation Time Constant of 165 ± 24 ms at −50 mV and V1/2 of −24 ± 2 mV, values which are consistent with previous reports for endogenous M-currents. In current clamp studies, these drugs also led to a depolarization of the resting membrane potential at values as negative as −60 mV. Flupirtine (10–20 μm), an M-current activator, caused a 3–14 mV leftward shift in the current–voltage relationship and also led to a hyperpolarization of resting membrane potential. These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages.

Cynthia L. Wladyka - One of the best experts on this subject based on the ideXlab platform.

  • kcnq m currents contribute to the resting membrane potential in rat visceral sensory neurons
    The Journal of Physiology, 2006
    Co-Authors: Cynthia L. Wladyka, Diana L Kunze
    Abstract:

    The M-current is a slowly activating, non-inactivating potassium current that has been shown to be present in numerous cell types. In this study, KCNQ2, Q3 and Q5, the molecular correlates of M-current in neurons, were identified in the visceral sensory neurons of the nodose ganglia from rats through immunocytochemical studies. All neurons showed expression of each of the three proteins. In voltage clamp studies, the cognition-enhancing drug linopirdine (1-50 microM) and its analogue, XE991 (10 microM), quickly and irreversibly blocked a small, slowly activating current that had kinetic properties similar to KCNQ/M-currents. This current activated between -60 and -55 mV, had a voltage-dependent activation Time Constant of 208 +/- 12 ms at -20 mV, a Deactivation Time Constant of 165 +/- 24 ms at -50 mV and V1/2 of -24 +/- 2 mV, values which are consistent with previous reports for endogenous M-currents. In current clamp studies, these drugs also led to a depolarization of the resting membrane potential at values as negative as -60 mV. Flupirtine (10-20 microM), an M-current activator, caused a 3-14 mV leftward shift in the current-voltage relationship and also led to a hyperpolarization of resting membrane potential. These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages.

  • KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons.
    The Journal of Physiology, 2006
    Co-Authors: Cynthia L. Wladyka, Diana L Kunze
    Abstract:

    The M-current is a slowly activating, non-inactivating potassium current that has been shown to be present in numerous cell types. In this study, KCNQ2, Q3 and Q5, the molecular correlates of M-current in neurons, were identified in the visceral sensory neurons of the nodose ganglia from rats through immunocytochemical studies. All neurons showed expression of each of the three proteins. In voltage clamp studies, the cognition-enhancing drug linopirdine (1–50 μm) and its analogue, XE991 (10 μm), quickly and irreversibly blocked a small, slowly activating current that had kinetic properties similar to KCNQ/M-currents. This current activated between −60 and −55 mV, had a voltage-dependent activation Time Constant of 208 ± 12 ms at −20 mV, a Deactivation Time Constant of 165 ± 24 ms at −50 mV and V1/2 of −24 ± 2 mV, values which are consistent with previous reports for endogenous M-currents. In current clamp studies, these drugs also led to a depolarization of the resting membrane potential at values as negative as −60 mV. Flupirtine (10–20 μm), an M-current activator, caused a 3–14 mV leftward shift in the current–voltage relationship and also led to a hyperpolarization of resting membrane potential. These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages.

Jacques M T De Bakker - One of the best experts on this subject based on the ideXlab platform.

  • Clinical research Arrhythmia/electrophysiology Pacemaker current (If) in the human sinoatrial node
    2015
    Co-Authors: Arie O Verkerk, Ronald Wilders, Ron J G Peters, Eli Broekhuis, Ruben Coronel, Jacques M T De Bakker, Kayan Lam, Hanno L. Tan
    Abstract:

    Aims Animal studies revealed that the hyperpolarization-activated pacemaker current, If, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. If is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that If is functionally present and contributes to pacemaking in human SAN. We aimed to study If properties in human SAN. Methods and results In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and If using patch-clamp techniques. Pace-maker cells generated spontaneous APs (cycle length 828+15 ms) following slow diastolic depolarization, maximal diastolic potential 261.7+4.3 mV, and maximal AP upstroke velocity 4.6+1.2 V/s. They exhibi-ted anhyperpolarization-activated inward current, blocked byexternal Csþ (2 mmol/L), characterizing it as If. Fully-activated conductancewas 75.2+3.8 pS/pF, reversal potential222.1+2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation 296.9+2.7 and 28.8+0.5 mV. Activation Time Constant ranged from 350 ms (2130 mV) to 1 s (2100 mV), Deactivation Time Constant 156+ 45 ms (240 mV). The role of If in pacemaker activity was demonstrated by slowing of pacemaker cell dias-tolic depolarization and beating rate by Csþ. Conclusion If is functionally expressed in human SAN and probably contributes to pacemaking in human SAN

  • pacemaker current if in the human sinoatrial node
    European Heart Journal, 2007
    Co-Authors: Arie O Verkerk, Ronald Wilders, Marcel M G J Van Borren, Ron J G Peters, Eli Broekhuis, Ruben Coronel, Jacques M T De Bakker
    Abstract:

    Aims Animal studies revealed that the hyperpolarization-activated pacemaker current, I f, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. I f is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that I f is functionally present and contributes to pacemaking in human SAN. We aimed to study I f properties in human SAN. Methods and results In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and I f using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 ± 15 ms) following slow diastolic depolarization, maximal diastolic potential − 61.7 ± 4.3 mV, and maximal AP upstroke velocity 4.6 ± 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs+ (2 mmol/L), characterizing it as I f. Fully-activated conductance was 75.2 ± 3.8 pS/pF, reversal potential − 22.1 ± 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation − 96.9 ± 2.7 and − 8.8 ± 0.5 mV. Activation Time Constant ranged from ∼350 ms (−130 mV) to ∼1 s (−100 mV), Deactivation Time Constant 156 ± 45 ms (−40 mV). The role of I f in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs+. Conclusion I f is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.

Arie O Verkerk - One of the best experts on this subject based on the ideXlab platform.

  • Clinical research Arrhythmia/electrophysiology Pacemaker current (If) in the human sinoatrial node
    2015
    Co-Authors: Arie O Verkerk, Ronald Wilders, Ron J G Peters, Eli Broekhuis, Ruben Coronel, Jacques M T De Bakker, Kayan Lam, Hanno L. Tan
    Abstract:

    Aims Animal studies revealed that the hyperpolarization-activated pacemaker current, If, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. If is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that If is functionally present and contributes to pacemaking in human SAN. We aimed to study If properties in human SAN. Methods and results In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and If using patch-clamp techniques. Pace-maker cells generated spontaneous APs (cycle length 828+15 ms) following slow diastolic depolarization, maximal diastolic potential 261.7+4.3 mV, and maximal AP upstroke velocity 4.6+1.2 V/s. They exhibi-ted anhyperpolarization-activated inward current, blocked byexternal Csþ (2 mmol/L), characterizing it as If. Fully-activated conductancewas 75.2+3.8 pS/pF, reversal potential222.1+2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation 296.9+2.7 and 28.8+0.5 mV. Activation Time Constant ranged from 350 ms (2130 mV) to 1 s (2100 mV), Deactivation Time Constant 156+ 45 ms (240 mV). The role of If in pacemaker activity was demonstrated by slowing of pacemaker cell dias-tolic depolarization and beating rate by Csþ. Conclusion If is functionally expressed in human SAN and probably contributes to pacemaking in human SAN

  • pacemaker current if in the human sinoatrial node
    European Heart Journal, 2007
    Co-Authors: Arie O Verkerk, Ronald Wilders, Marcel M G J Van Borren, Ron J G Peters, Eli Broekhuis, Ruben Coronel, Jacques M T De Bakker
    Abstract:

    Aims Animal studies revealed that the hyperpolarization-activated pacemaker current, I f, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. I f is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that I f is functionally present and contributes to pacemaking in human SAN. We aimed to study I f properties in human SAN. Methods and results In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and I f using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 ± 15 ms) following slow diastolic depolarization, maximal diastolic potential − 61.7 ± 4.3 mV, and maximal AP upstroke velocity 4.6 ± 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs+ (2 mmol/L), characterizing it as I f. Fully-activated conductance was 75.2 ± 3.8 pS/pF, reversal potential − 22.1 ± 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation − 96.9 ± 2.7 and − 8.8 ± 0.5 mV. Activation Time Constant ranged from ∼350 ms (−130 mV) to ∼1 s (−100 mV), Deactivation Time Constant 156 ± 45 ms (−40 mV). The role of I f in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs+. Conclusion I f is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.

Yoshio Watanabe - One of the best experts on this subject based on the ideXlab platform.

  • Selective block of delayed rectifying potassium current in the rabbit sinoatrial node by a novel class III antiarrhythmic agent MS-551
    Heart and Vessels, 1994
    Co-Authors: Tomoaki Saeki, Masao Nishimura, Christopher H. Follmer, Yoshio Watanabe
    Abstract:

    Electrophysiological actions of MS-551, a novel class III antiarrhythmic agent, were studied using small preparations (0.2 × 0.2 × 0.1mm) of the rabbit sinoatrial (SA) node. MS-551 (0.1–3 µM) exerted a negative chronotropic action by prolonging the action potential duration and diastolic interval. Automaticity was completely suppressed in 5 of 6 preparations at 1–3 µM. Voltage clamp experiments using double microelectrode techniques revealed that MS-551 (0.1–10µM) blocked the delayed rectifying K^+ current (I_K) in a concentration-dependent manner, and the block was almost saturated at >1 µM, attaining 60% ± 10% at 10 µM ( n = 5). The MS-551-sensitive I_K tail (K_d = 0.4µM, Hill r = 1.4, n = 5) had fast and slow components of Deactivation. MS-551 (1 µM) reduced the amplitudes of control I_K fast and I_K slow from 20 ± 4 and 11 ± 4 nA to 8 ± 3 and 5 ± 3 nA, respectively ( P < 0.01, n = 4). Although the fast Deactivation Time Constant at −60mV remained unaltered (127 ± 12 vs 113 ± 13ms), the slow Deactivation Time Constant was prolonged from 1,117 ± 130 to 1,555 ± 407ms by 1µM MS-551 ( P < 0.05). This agent shifted the steady-state activation curve for I_K from −21 ± 2 to −26 ± 4mV and increased the slope factor from 8 ± 1 to 9 ± 1mV ( P < 0.05, n = 4). The fully-activated I_K exhibited prominent inward rectification and was reduced by MS-551. These results suggest that (1) MS-551 prolongs the action potential duration and diastolic interval, and exerts a negative chronotropic action by blocking I_K, (2) MS-551 has a higher affinity for the activated than the resting state K^+ channel, and (3) this agent may either preferentially block one type of I_K, or stabilize a single population of I_K in a subconductance state in the rabbit SA node.