Nanodomains of single Ca2+ channels contribute to action potential repolarization in cortical neurons

2007 ◽  
pp. 31-32
Keyword(s):  
Action Potential ◽  
Cortical Neurons ◽  
Action Potential Repolarization ◽  
Ca2 Channels

scholarly journals Nanodomains of Single Ca2+ Channels Contribute to Action Potential Repolarization in Cortical Neurons

2007 ◽  
Vol 27 (3) ◽  
pp. 483-495 ◽  
Author(s):  
A. Muller ◽  
M. Kukley ◽  
M. Uebachs ◽  
H. Beck ◽  
D. Dietrich
Keyword(s):  
Action Potential ◽  
Cortical Neurons ◽  
Action Potential Repolarization ◽  
Ca2 Channels

scholarly journals Differential Inhibition of Ca2+ Channels by α2-Adrenoceptors in Three Functional Subclasses of Rat Sympathetic Neurons

2008 ◽  
Vol 100 (6) ◽  
pp. 3055-3063 ◽  
Author(s):  
Chen Li ◽  
John P. Horn
Keyword(s):  
Action Potential ◽  
Sympathetic Neurons ◽  
Input Resistance ◽  
Cell Types ◽  
Resting Potential ◽  
Cell Groups ◽  
Cervical Ganglion ◽  
Experimental Criterion ◽  
Action Potential Repolarization ◽  
Ca2 Channels

A comparison of identified sympathetic neurons in the isolated intact superior cervical ganglion revealed that secretomotor, pilomotor, and vasoconstrictor cells differ in their action potential mechanisms and in their postsynaptic α2-adrenergic responses to 10 μM norepinephrine (NE). In normal saline, the half-width of the spike afterhyperpolarization (AHP) in secretomotor neurons (103.5 ± 6.2 ms) was twofold that recorded in vasoconstrictor neurons (47.7 ± 2.9 ms) and 1.5-fold that in pilomotor neurons (71.4 ± 10.3 ms). Bath-applied NE reversibly inhibited the action potential repolarization shoulder, AHP amplitude, and AHP duration in secretomotor and pilomotor neurons to a similar extent, but had no effect on vasoconstrictor neurons. The insensitivity of vasomotor neurons to NE was not an artifact produced by microelectrode recording because all three cell groups were similar in terms of resting potential and input resistance. Moreover, NE insensitivity was not a natural consequence of briefer AHP duration in vasoconstrictor cells. Adding 10 mM TEA+ caused marked accentuation of the shoulder and AHP duration in vasoconstrictor neurons and comparable changes in the other two cell types, but did not unmask any sign of NE sensitivity in the vasoconstrictors. However, the spike shoulder and AHP in vasoconstrictors were Cd2+ sensitive, blocked by ω-conotoxin, an N-type calcium channel antagonist, and inhibited by oxotremorine-M, a muscarinic receptor agonist. These data show that NE can differentially modulate functional subsets of mammalian sympathetic neurons and that NE insensitivity can serve as a practical experimental criterion for identification of vasomotor neurons in the isolated ganglion.

scholarly journals Ceramide modulates HERG potassium channel gating by translocation into lipid rafts

2010 ◽  
Vol 299 (1) ◽  
pp. C74-C86 ◽  
Author(s):  
Sindura B. Ganapathi ◽  
Todd E. Fox ◽  
Mark Kester ◽  
Keith S. Elmslie
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Lipid Rafts ◽  
Negative Impact ◽  
Cardiac Action Potential ◽  
Cholesterol Depletion ◽  
Cardiac Action ◽  
Herg Channels ◽  
The Impact ◽  
Action Potential Repolarization

Human ether-à-go-go-related gene (HERG) potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of cancers, making it an attractive target for cancer therapy. Ceramide is an important second messenger of the sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an anticancer agent . Yet the acute effects of ceramide on HERG potassium channels are not known. In the present study we examined the effects of cell-permeable C6-ceramide on HERG potassium channels stably expressed in HEK-293 cells. C6-ceramide (10 μM) reversibly inhibited HERG channel current (IHERG) by 36 ± 5%. Kinetically, ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (Δ V1/2 = −8 ± 0.5 mV) and increased the deactivation rate (43 ± 3% for τfast and 51 ± 3% for τslow). Mechanistically, ceramide recruited HERG channels within caveolin-enriched lipid rafts. Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of C6-ceramide on HERG channels and suggest that C6-ceramide can be a promising therapeutic for cancers that overexpress HERG.

Guinea pig visceral C-fiber neurons are diverse with respect to the K+ currents involved in action-potential repolarization

1994 ◽  
Vol 71 (2) ◽  
pp. 561-574 ◽  
Author(s):  
E. P. Christian ◽  
J. Togo ◽  
K. E. Naper
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Outward Current ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Whole Cell ◽  
C Fiber ◽  
K Current ◽  
Action Potential Repolarization

1. Intracellular recordings were made from C-fiber neurons identified by antidromic conduction velocity in intact guinea pig nodose ganglia maintained in vitro, and whole-cell patch clamp recordings were made from dissociated guinea pig nodose neurons to investigate the contribution of various K+ conductances to action-potential repolarization. 2. The repolarizing phase of the intracellularly recorded action potential was prolonged in a concentration-dependent manner by charybdotoxin (Chtx; EC50 = 39 nM) or iberiatoxin (Ibtx; EC50 = 48 nM) in a subpopulation of 16/36 C-fiber neurons. In a subset of these experiments, removal of extracellular Ca2+ reversibly prolonged action-potential duration (APD) in the same 4/9 intracellularly recorded C-fiber neurons affected by Chtx (> or = 100 nM). These convergent results support that a Ca(2+)-activated K+ current (IC) contributes to action-potential repolarization in a restricted subpopulation of C-fiber neurons. 3. Tetraethylammonium (TEA; 1-10 mM) increased APD considerably further in the presence of 100-250 nM Chtx or Ibtx, or in nominally Ca(2+)-free superfusate in 14/14 intracellularly recorded C-fiber neurons. TEA affected APD similarly in subpopulations of neurons with and without IC, suggesting that a voltage-dependent K+ current (IK) contributes significantly to action-potential repolarization in most nodose C-fiber neurons. 4. Substitution of Mn2+ for Ca2+ reduced outward whole-cell currents elicited by voltage command steps positive to -30 mV (2-25 ms) in a subpopulation of 21/36 dissociated nodose neurons, supporting the heterogeneous expression of IC. The kinetics of outward tail current relaxations (tau s of 1.5-2 ms) measured at the return of 2-3 ms depolarizing steps to -40 mV were indistinguishable in neurons with and without IC, precluding a separation of the nodose IC and IK by a difference in deactivation rates. 5. Chtx (10-250 nM) reduced in a subpopulation of 3/8 C-fiber neurons the total outward current elicited by voltage steps depolarized to -30 mV in single microelectrode voltage-clamp recordings. TEA (5-10 mM) further reduced outward current in the presence of 100-250 nM Chtx in all eight experiments. The Chtx-sensitive current was taken to represent IC, and the TEA-sensitive current, the IK component contributing to action-potential repolarization. 6. Rapidly inactivating current (IA) was implicated in action-potential repolarization in a subpopulation of intracellularly recorded C-fiber neurons. In 4/7 neurons, incremented hyperpolarizing prepulses negative to -50 mV progressively shortened APD.(ABSTRACT TRUNCATED AT 400 WORDS)

High Safety Factor for Action Potential Conduction Along Axons But Not Dendrites of Cultured Hippocampal and Cortical Neurons

1998 ◽  
Vol 80 (4) ◽  
pp. 2089-2101 ◽  
Author(s):  
Paul J. Mackenzie ◽  
Timothy H. Murphy
Keyword(s):  
Action Potential ◽  
Safety Factor ◽  
Cortical Neurons ◽  
Neuronal Firing ◽  
Repetitive Firing ◽  
Current Clamp ◽  
Similar Reduction ◽  
Axonal Conduction ◽  
Cultured Cortical Neurons ◽  
20 Nm

Mackenzie, Paul J. and Timothy H. Murphy. High safety factor for action potential conduction along axons but not dendrites of cultured hippocampal and cortical neurons. J. Neurophysiol. 80: 2089–2101, 1998. By using a combination of Ca2+ imaging and current-clamp recording, we previously reported that action potential (AP) conduction is reliably observed from the soma to axonal terminals in cultured cortical neurons. To extend these studies, we evaluated Ca2+ influx evoked by Na+ APs as a marker of AP conduction under conditions that are expected to lower the conduction safety factor to explore mechanisms of axonal and dendritic excitability. As expected, reducing the extracellular Na+ concentration from 150 to ∼60 mM decreased the amplitude of APs recorded in the soma but surprisingly did not influence axonal conduction, as monitored by measuring Ca2+ transients. Furthermore, reliable axonal conduction was observed in dilute (20 nM) tetrodotoxin (TTX), despite a similar reduction in AP amplitude. In contrast, the Ca2+ transient measured along dendrites was markedly reduced in low Na+, although still mediated by TTX-sensitive Na+ channels. Dendritic action-potential evoked Ca2+ transients were also markedly reduced in 20 nM TTX. These data provide further evidence that strongly excitable axons are functionally compartmentalized from weakly excitable dendrites. We conclude that modulation of Na+ currents or membrane potential by neurotransmitters or repetitive firing is more likely to influence neuronal firing before AP generation than the propagation of signals to axonal terminals. In contrast, the relatively low safety factor for back-propagating APs in dendrites would suggest a stronger effect of Na+ current modulation.

Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons

1993 ◽  
Vol 69 (6) ◽  
pp. 2150-2163 ◽  
Author(s):  
F. Viana ◽  
D. A. Bayliss ◽  
A. J. Berger
Keyword(s):  
Action Potential ◽  
Calcium Influx ◽  
Potassium Conductance ◽  
Firing Frequency ◽  
Neonatal Rat ◽  
Repetitive Firing ◽  
Firing Behavior ◽  
Hypoglossal Motoneurons ◽  
Potassium Conductances ◽  
Action Potential Repolarization

1. The role of multiple potassium conductances in action potential repolarization and repetitive firing behavior of hypoglossal motoneurons was investigated using intracellular recording techniques in a brain stem slice preparation of the neonatal rat (0-15 days old). 2. The action potential was followed by two distinct afterhyperpolarizations (AHPs). The early one was of short duration and is termed the fAHP; the later AHP was of longer duration and is termed the mAHP. The amplitudes of both AHPs were enhanced by membrane potential depolarization (further from EK). In addition, their amplitudes were reduced by high extracellular K+ concentration, suggesting that activation of potassium conductances underlies both phases of the AHP. 3. Prolongation of the action potential and blockade of the fAHP were observed after application of 1) tetraethylammonium (TEA) (1-10 mM) and 2) 4-aminopyridine (4-AP) (0.1-0.5 mM). Calcium channel blockers had little or no effect on the fAHP or action potential duration. 4. The size of the mAHP was diminished by 1) manganese, 2) lowering external Ca2+, 3) apamin, and 4) intracellular injection of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) suggesting that influx of calcium activates the potassium conductance that underlies the mAHP. 5. The mAHP was unaffected by nifedipine (20 microM), but was strongly reduced by focal application of omega-conotoxin GVIA, suggesting that N-type calcium channels represent the major calcium influx pathway for activation of the calcium-dependent K+ conductance underlying the mAHP. 6. Repetitive firing properties were investigated by injecting long-duration depolarizing current pulses. Steady-state firing rose linearly with injected current amplitude. The slope of the firing frequency-current (f-I) relationship averaged approximately 30 Hz/nA in control conditions. Blockade of the conductance underlying the mAHP caused a marked increase in the minimal repetitive firing frequency and in the slope of the f-I plot, indicating a prominent role for the conductance underlying the mAHP in controlling repetitive firing behavior. 7. We conclude that action potential repolarization and AHPs are due to activation of pharmacologically distinct potassium conductances. Whereas repolarization of the action potential and the fAHP involves primarily a voltage-dependent, calcium-independent potassium conductance that is TEA- and 4-AP-sensitive, the mAHP requires the influx of extracellular calcium and is apamin sensitive. Activation of the calcium-activated potassium conductance greatly influences the normal repetitive firing of neonatal hypoglossal motoneurons.

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