MCP-1 Enhances Excitability of Nociceptive Neurons in Chronically Compressed Dorsal Root Ganglia

2006 ◽  
Vol 96 (5) ◽  
pp. 2189-2199 ◽  
Author(s):  
J. H. Sun ◽  
B. Yang ◽  
D. F. Donnelly ◽  
C. Ma ◽  
R. H. LaMotte
Keyword(s):  
Dorsal Root ◽  
Reversal Potential ◽  
Outward Current ◽  
Peak Height ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nociceptive Neurons ◽  
Voltage Dependent ◽  
Ionic Mechanisms

Previous experimental results from our laboratory demonstrated that monocyte chemoattractant protein-1 (MCP-1) depolarizes or increases the excitability of nociceptive neurons in the intact dorsal root ganglion (DRG) after a chronic compression of the DRG (CCD), an injury that upregulates neuronal expression of both MCP-1 and mRNA for its receptor CCR2. We presently explore the ionic mechanisms underlying the excitatory effects of MCP-1. MCP-1 (100 nM) was applied, after CCD, to acutely dissociated small DRG neurons with nociceptive properties. Under current clamp, the proportion of neurons depolarized was similar to that previously observed for CCD-treated neurons in the intact ganglion, although the magnitude of depolarization was greater. MCP-1 induced a decrease in rheobase by 44 ± 10% and some cells became spontaneously active at resting potential. Action potential width at a voltage equal to 10% of the peak height was increased from 4.94 ± 0.23 to 5.90 ± 0.47 ms. In voltage clamp, MCP-1 induced an inward current in 27 of 50 neurons held at −60 mV, which increased with concentration over the range of 3 to 300 nM (EC50= 45 nM). The MCP-1–induced current was not voltage dependent and had an estimated reversal potential of −27 mV. In addition, MCP-1 inhibited a voltage-dependent, noninactivating outward current, presumably a delayed rectifier type K+conductance. We conclude that MCP-1 enhances excitability in CCD neurons by, at least, two mechanisms: 1) activation of a nonvoltage-dependent depolarizing current with characteristics similar to a nonselective cation conductance and 2) inhibition of a voltage-dependent outward current.

scholarly journals Permeation of Na+ through a delayed rectifier K+ channel in chick dorsal root ganglion neurons.

1994 ◽  
Vol 104 (4) ◽  
pp. 747-771 ◽  
Author(s):  
M J Callahan ◽  
S J Korn
Keyword(s):  
Dorsal Root Ganglion ◽  
Binding Site ◽  
Dorsal Root ◽  
Reversal Potential ◽  
Dorsal Root Ganglion Neurons ◽  
K Channel ◽  
Delayed Rectifier ◽  
Cation Binding Site ◽  
Voltage Dependent ◽  
Ganglion Neurons

In whole-cell patch clamp recordings from chick dorsal root ganglion neurons, removal of intracellular K+ resulted in the appearance of a large, voltage-dependent inward tail current (Icat). Icat was not Ca2+ dependent and was not blocked by Cd2+, but was blocked by Ba2+. The reversal potential for Icat shifted with the Nernst potential for [Na+]. The channel responsible for Icat had a cation permeability sequence of Na+ > Li+ > TMA+ > NMG+ (PX/PNa = 1:0.33:0.1:0) and was impermeable to Cl-. Addition of high intracellular concentrations of K+, Cs+, or Rb+ prevented the occurrence of Icat. Inhibition of Icat by intracellular K+ was voltage dependent, with an IC50 that ranged from 3.0-8.9 mM at membrane potentials between -50 and -110 mV. This voltage-dependent shift in IC50 (e-fold per 52 mV) is consistent with a single cation binding site approximately 50% of the distance into the membrane field. Icat displayed anomolous mole fraction behavior with respect to Na+ and K+; Icat was inhibited by 5 mM extracellular K+ in the presence of 160 mM Na+ and potentiated by equimolar substitution of 80 mM K+ for Na+. The percent inhibition produced by both extracellular and intracellular K+ at 5 mM was identical. Reversal potential measurements revealed that K+ was 65-105 times more permeant than Na+ through the Icat channel. Icat exhibited the same voltage and time dependence of inactivation, the same voltage dependence of activation, and the same macroscopic conductance as the delayed rectifier K+ current in these neurons. We conclude that Icat is a Na+ current that passes through a delayed rectifier K+ channel when intracellular K+ is reduced to below 30 mM. At intracellular K+ concentrations between 1 and 30 mM, PK/PNa remained constant while the conductance at -50 mV varied from 80 to 0% of maximum. These data suggest that the high selectivity of these channels for K+ over Na+ is due to the inability of Na+ to compete with K+ for an intracellular binding site, rather than a barrier that excludes Na+ from entry into the channel or a barrier such as a selectivity filter that prevents Na+ ions from passing through the channel.

scholarly journals A whole-cell and single-channel study of the voltage-dependent outward potassium current in avian hepatocytes.

1988 ◽  
Vol 91 (2) ◽  
pp. 255-274 ◽  
Author(s):  
C Marchetti ◽  
R T Premont ◽  
A M Brown
Keyword(s):  
Single Channel ◽  
Reversal Potential ◽  
Outward Current ◽  
Single Type ◽  
K Channel ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Voltage Dependent ◽  
Single Channel Currents ◽  
K Currents

Voltage-dependent membrane currents were studied in dissociated hepatocytes from chick, using the patch-clamp technique. All cells had voltage-dependent outward K+ currents; in 10% of the cells, a fast, transient, tetrodotoxin-sensitive Na+ current was identified. None of the cells had voltage-dependent inward Ca2+ currents. The K+ current activated at a membrane potential of about -10 mV, had a sigmoidal time course, and did not inactivate in 500 ms. The maximum outward conductance was 6.6 +/- 2.4 nS in 18 cells. The reversal potential, estimated from tail current measurements, shifted by 50 mV per 10-fold increase in the external K+ concentration. The current traces were fitted by n2 kinetics with voltage-dependent time constants. Omitting Ca2+ from the external bath or buffering the internal Ca2+ with EGTA did not alter the outward current, which shows that Ca2+-activated K+ currents were not present. 1-5 mM 4-aminopyridine, 0.5-2 mM BaCl2, and 0.1-1 mM CdCl2 reversibly inhibited the current. The block caused by Ba was voltage dependent. Single-channel currents were recorded in cell-attached and outside-out patches. The mean unitary conductance was 7 pS, and the channels displayed bursting kinetics. Thus, avian hepatocytes have a single type of K+ channel belonging to the delayed rectifier class of K+ channels.

Inward rectification in the inner segment of single retinal cone photoreceptors

1990 ◽  
Vol 64 (6) ◽  
pp. 1917-1928 ◽  
Author(s):  
A. V. Maricq ◽  
J. I. Korenbrot
Keyword(s):  
Voltage Dependence ◽  
Reversal Potential ◽  
Input Resistance ◽  
Resting Potential ◽  
Inward Rectification ◽  
Delayed Rectifier ◽  
Light Illumination ◽  
Cone Photoreceptors ◽  
Voltage Dependent ◽  
Kinetics Of

1. Single cone photoreceptors were dissociated from the retina of a lizard with the aid of papain. The majority of the cells lost their outer segments but had well-preserved, large synaptic pedicles. Electrical properties of the cells were studied with tight-seal electrodes in the whole cell configuration. On the average, cone inner segments had a resting potential of -55 mV, and at this potential their input resistance was 2.6 G omega and their capacitance was 8 pF. 2. Under current clamp the cones exhibited a pronounced anomalous voltage rectification in response to hyperpolarizing currents. The voltage rectification was eliminated by external Cs+. 3. The Cs(+)-sensitive current underlying voltage rectification was isolated by blocking other currents present in the cone. Co2+ blocked a voltage-dependent Ca2+ current and a Ca2(+)-dependent Cl- current, and tetraethylammonium (TEA)+ blocked a delayed-rectifier K+ current. 4. The Cs(+)-sensitive current was activated by hyperpolarization to potentials more negative than -50 mV, and its current-voltage (I-V) relationship exhibited inward rectification. 5. The inward-rectifying current was selective for K+, but not exclusively. Increasing external K+ concentration 10-fold shifted the reversal potential by 13 mV. If Na ions also permeate through the inward-rectifying channels, the ratio of permeabilities (PK+/PNa+) in normal solution is approximately 3.9. 6. The kinetics of the inward-rectifying current were described by the sum of two exponentials, the amplitudes and time constants of which were voltage dependent. 7. The voltage dependence of the inward-rectifying current was described by Boltzmann's function, with half-maximum activation at -79 mV and a steepness parameter of 7.5 mV. 8. The voltage dependence and kinetics of the inward-rectifying current suggest that it is inactive in a cone photoreceptor in the dark. However, it becomes activated in the course of large hyperpolarizations generated by bright-light illumination. This activity will modify the waveform of the photovoltage--the current will generate a depolarizing component that opposes the light-generated hyperpolarization.

Mechanisms of neocortical epileptogenesis in vitro

1982 ◽  
Vol 48 (6) ◽  
pp. 1321-1335 ◽  
Author(s):  
M. J. Gutnick ◽  
B. W. Connors ◽  
D. A. Prince
Keyword(s):  
Reversal Potential ◽  
Excitatory Input ◽  
Short Latency ◽  
Resting Potential ◽  
Excitatory Postsynaptic Potential ◽  
Cellular Mechanisms ◽  
Voltage Dependent ◽  
Intact Cortex

1. The cellular mechanisms underlying interictal epileptogenesis have been examined in an in vitro slice preparation of guinea pig neocortex. Penicillin or bicuculline was applied to the tissue, and intracellular recordings were obtained from neurons and glia. 2. Following convulsant application, stimulation could elicit a short-latency excitatory postsynaptic potential (EPSP) and a large, longer latency depolarization shift (DS) in single neurons. DSs in neurons of the slice were very similar to those evoked in neurons of neocortex in vivo in that they displayed an all-or-none character, large shifts in latency during repetitive stimuli, long afterpotentials, and a prolonged refractory period. In contrast to epileptogenesis produced by penicillin in intact cortex, neither spontaneous DSs nor ictal episodes were observed in neocortical slices. 3. In simultaneous recordings from pairs of neurons within the same cortical column, DS generation and latency shifts were invariably synchronous. DS generation in neurons was also coincident with large, paroxysmal increases of extracellular [K+], as indicated by simultaneous recordings from glia. 4. When polarizing currents were applied to neurons injected with the local anesthetic QX-314, the DS amplitude varied monotonically and had an extrapolated reversal potential near 0 mV. In neurons injected with the K+-current blocker Cs+, large displacements of membrane potential were possible, and both the short-latency EPSP and the peak of the DS diminished completely at about 0 mV. At potentials positive to this, the short-latency EPSP was reversed, and the DS was replaced by a paroxysmal hyperpolarization whose rise time and peak latency were prolonged compared to the DS evoked at resting potential. The paroxysmal hyperpolarization probably represents the prolonged activation of the impaled neuron by EPSPs. 5. Voltage-dependent components, including slow spikes, appeared to contribute to generation of the DS at resting potential in Cs+-filled cells, and these components were blocked during large depolarizations. 6. The results suggest that DS generation in single neocortical neurons occurs during synchronous synaptic activation of a large group of cells. DS onset in a given neuron is determined by the timing of a variable-latency excitatory input that differs from the short-latency EPSP. The DS slow envelope appears to be generated by long-duration excitatory synaptic currents and may be modulated by intrinsic voltage-dependent membrane conductances. 7. We present a hypothesis for the initiation of the DS, based on the anatomical and physiological organization of the intrinsic neocortical circuits.

Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization

2000 ◽  
Vol 278 (3) ◽  
pp. H806-H817 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Ventricular Repolarization ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Voltage Dependent

Although inactivation of the rapidly activating delayed rectifier current ( I Kr) limits outward current on depolarization, the role of I Kr (and recovery from inactivation) during repolarization is uncertain. To characterize I Krduring ventricular repolarization (and compare with the inward rectifier current, I K1), voltage-clamp waveforms simulating the action potential were applied to canine ventricular, atrial, and Purkinje myocytes. In ventricular myocytes, I Kr was minimal at plateau potentials but transiently increased during repolarizing ramps. The I Kr transient was unaffected by repolarization rate and maximal after 150-ms depolarizations (+25 mV). Action potential clamps revealed the I Kr transient terminating the plateau. Although peak I Kr transient density was relatively uniform among myocytes, potentials characterizing the peak transients were widely dispersed. In contrast, peak inward rectifier current ( I K1) density during repolarization was dispersed, whereas potentials characterizing I K1 defined a narrower (more negative) voltage range. In summary, rapidly activating I Kr provides a delayed voltage-dependent (and functionally time-independent) outward transient during ventricular repolarization, consistent with rapid recovery from inactivation. The heterogeneous voltage dependence of I Kr provides a novel means for modulating the contribution of this current during repolarization.

Modulation of the delayed rectifier, IK, by cadmium in cat ventricular myocytes

1992 ◽  
Vol 262 (1) ◽  
pp. C75-C83 ◽  
Author(s):  
C. H. Follmer ◽  
N. J. Lodge ◽  
C. A. Cullinan ◽  
T. J. Colatsky
Keyword(s):  
Voltage Clamp ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Membrane Potentials ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Control Value ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Slope Factor

The effects of cadmium on the delayed outward potassium current (IK) were investigated in isolated cat ventricular myocytes using the single suction pipette voltage-clamp technique. IK activation was examined using peak tail currents elicited after 750-ms voltage-clamp steps to selected membrane potentials from a holding potential of -40 mV. In the presence of Cd2+ (0.2 mM), peak tail currents increased from a control value of 85 +/- 12 to 125 +/- 18 pA (n = 4). Activation curves constructed from the average peak tail-current measurements in all experiments showed that Cd2+ shifted the voltage dependence of activation to more positive potentials by 16.4 +/- 2.0 mV and increased the slope factor of the activation curve from 6.1 +/- 0.2 to 6.9 +/- 0.2 mV. In the absence of Cd2+, increases in holding potential from -30 to -70 mV had no effect on the magnitude of the peak tail currents, suggesting that the Cd(2+)-induced increase was not the result of a voltage-dependent increase in the number of available K+ channels at the holding potential. Slow voltage ramps from -70 to +70 mV revealed that Cd2+ increased the outward current at membrane potentials positive to +20 mV and shifted the voltage range in which IK inwardly rectified to more positive potentials. The fully activated current-voltage relationship was also shifted to more positive potentials by Cd2+. Cd2+ did not alter channel selectivity for K+.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium.

1986 ◽  
Vol 88 (6) ◽  
pp. 777-798 ◽  
Author(s):  
J R Hume ◽  
W Giles ◽  
K Robinson ◽  
E F Shibata ◽  
R D Nathan ◽  
...  
Keyword(s):  
Time Course ◽  
Voltage Dependence ◽  
Outward Current ◽  
Cardiac Cells ◽  
Delayed Rectifier ◽  
Mechanical Dispersion ◽  
Atrial Cells ◽  
Voltage Dependent ◽  
K Current ◽  
Kinetics Of

Individual myocytes were isolated from bullfrog atrium by enzymatic and mechanical dispersion, and a one-microelectrode voltage clamp was used to record the slow outward K+ currents. In normal [K+]o (2.5 mM), the slow outward current tails reverse between -95 and -100 mV. This finding, and the observed 51-mV shift of Erev/10-fold change in [K+]o, strongly suggest that the "delayed rectifier" in bullfrog atrial cells is a K+ current. This current, IK, plays an important role in initiating repolarization, and it is distinct from the quasi-instantaneous, inwardly rectifying background current, IK. In atrial cells, IK does not exhibit inactivation, and very long depolarizing clamp steps (20 s) can be applied without producing extracellular K+ accumulation. The possibility of [K+]o accumulation contributing to these slow outward current changes was assessed by (a) comparing reversal potentials measured after short (2 s) and very long (15 s) activating prepulses, and (b) studying the kinetics of IK at various holding potentials and after systematically altering [K+]o. In the absence of [K+]o accumulation, the steady state activation curve (n infinity) and fully activated current-voltage (I-V) relation can be obtained directly. The threshold of the n infinity curve is near -50 mV, and it approaches a maximum at +20 mV; the half-activation point is approximately -16 mV. The fully activated I-V curve of IK is approximately linear in the range -40 to +30 mV. Semilog plots of the current tails show that each tail is a single-exponential function, which suggests that only one Hodgkin-Huxley conductance underlies this slow outward current. Quantitative analysis of the time course of onset of IK and of the corresponding envelope of tails demonstrate that the activation variable, n, must be raised to the second power to fit the sigmoid onset accurately. The voltage dependence of the kinetics of IK was studied by recording and curve-fitting activating and deactivating (tail) currents. The resulting 1/tau n curve is U-shaped and somewhat asymmetric; IK exhibits strong voltage dependence in the diastolic range of potentials. Changes in the [Ca2+]o in the superfusing Ringer's, and/or addition of La3+ to block the transmembrane Ca2+ current, show that the time course and magnitude of IK are not significantly modulated by transmembrane Ca2+ movements, i.e., by ICa. These experimentally measured voltage- and time-dependent descriptors of IK strongly suggest an important functional role for IK in atrial tissue: it initiates repolarization and can be an important determinant of rate-induced changes in action potential duration.

Potassium channel diversity within the muscular components of the feline lower esophageal sphincter

2004 ◽  
Vol 82 (11) ◽  
pp. 1006-1017 ◽  
Author(s):  
Anne Marie F Salapatek ◽  
Junzhi Ji ◽  
Ahmad Muinuddin ◽  
Nicholas E Diamant
Keyword(s):  
Lower Esophageal Sphincter ◽  
Circular Muscle ◽  
Outward Current ◽  
Resting Membrane Potential ◽  
Delayed Rectifier ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Esophageal Smooth Muscle Cells ◽  
Esophageal Sphincter ◽  
Resting Tone

We hypothesized that regional differences in electrophysiological properties exist within the musculature of the feline lower esophageal sphincter (LES) and that they may potentially contribute to functional asymmetry within the LES. Freshly isolated esophageal smooth muscle cells (SMCs) from the circular muscle and sling regions within the LES were studied under a patch clamp. The resting membrane potential (RMP) of the circular SMCs was significantly more depolarized than was the RMP of the sling SMCs, resulting from a higher Na+and Cl–permeability in circular muscle than in sling muscle. Large conductance Ca2+-activated K+(BKCa) set the RMP at both levels, since specific BKCainhibitors caused depolarization; however, BKCadensity was greatest in the circular region. A significant portion of the outward current was due to non-BKCa, especially in sling muscle, and likely delayed rectifier K+channels (KDR). There was a large reduction in outward current with 4-aminopyridine (4-AP) in sling muscle, while BKCablockers had a limited effect on the voltage-activated outward current in sling muscle. Differences in BKCa:KDRchannel ratios were also manifest by a leftward shift in the voltage-dependent activation curve in circular cells compared to sling cells. The electrophysiological differences seen between the circular and sling muscles provide a basis for their different contributions to LES activities such as resting tone and neurotransmitter responsiveness, and in turn could impart asymmetric drug responses and provide specific therapeutic targets.Key words: esophagus, esophageal motility, gastroesophageal reflux, KCa, KDR, LES tone.

scholarly journals Voltage-dependent conductances in Limulus ventral photoreceptors.

1982 ◽  
Vol 79 (2) ◽  
pp. 187-209 ◽  
Author(s):  
J E Lisman ◽  
G L Fain ◽  
P M O'Day
Keyword(s):  
Outward Current ◽  
Delayed Rectifier ◽  
Molluscan Neurons ◽  
Inward Current ◽  
Transient Component ◽  
Outward Currents ◽  
Voltage Dependent ◽  
Inward Currents ◽  
K Current ◽  
A Current

The voltage-dependent conductances of Limulus ventral photoreceptors have been investigated using a voltage-clamp technique. Depolarization in the dark induces inward and outward currents. The inward current is reduced by removing Na+ or Ca2+ and is abolished by removing both ions. These results suggest that both Na+ and Ca2+ carry voltage-dependent inward current. Inward current is insensitive to tetrodotoxin but is blocked by external Ni2+. The outward current has a large transient component that is followed by a smaller maintained component. Intracellular tetraethylammonium preferentially reduces the maintained component, and extracellular 4-amino pyridine preferentially reduces the transient component. Neither component is strongly affected by removal of extracellular Ca2+ or by intracellular injection of EGTA. It is concluded that the photoreceptors contain at least three separate voltage-dependent conductances: 1) a conductance giving rise to inward currents; 2) a delayed rectifier giving rise to maintained outward K+ current; and 3) a rapidly inactivating K+ conductance similar to the A current of molluscan neurons.

scholarly journals Outward current in single smooth muscle cells of the guinea pig taenia coli.

1989 ◽  
Vol 93 (3) ◽  
pp. 551-564 ◽  
Author(s):  
Y Yamamoto ◽  
S L Hu ◽  
C Y Kao
Keyword(s):  
Guinea Pig ◽  
Time Constant ◽  
Time Course ◽  
Reversal Potential ◽  
Outward Current ◽  
Enzymatic Digestion ◽  
Taenia Coli ◽  
Physiological Conditions ◽  
Dependent Component ◽  
Voltage Dependent

In single myocytes of the guinea pig taenia coli, dispersed by enzymatic digestion, the late outward current is carried by K+. It has both a Ca2+-activated component and a voltage-dependent component which is resistant to external Co2+. The reversal potential is -84 mV, and the channel(s) for it are highly selective to K+. At 33 degrees C, the activation follows n2 kinetics, with a voltage-dependent time constant of 10.6 ms at 0 mV, which shortens to 1.7 ms at +70 mV. Deactivation follows a single-exponential time course, with a voltage-dependent time constant of 11 ms at -50 mV, which lengthens to 33 ms at -20 mV. During a 4.5-s maintained depolarization, IK inactivates, most of it into two exponential components, but there is a small noninactivating residue. It is surmised that during an action potential under physiological conditions, there is sufficient IK to cause repolarization.

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