scholarly journals Monoterpenoid Terpinen-4-ol Exhibits Anticonvulsant Activity in Behavioural and Electrophysiological Studies

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Franklin F. F. Nóbrega ◽  
Mirian G. S. S. Salvadori ◽  
Cintia J. Masson ◽  
Carlos F. Mello ◽  
Tiago S. Nascimento ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Sodium Current ◽  
Anticonvulsant Effect ◽  
Aromatic Plants ◽  
Gabaergic Neurotransmission ◽  
Benzodiazepine Binding ◽  
Voltage Dependent ◽  
Electrophysiological Studies ◽  
Anticonvulsant Effects

Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 μL. For in vitro experiments, 4TRP concentrations were 0.1 mM and 1.0 mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of theGABAAreceptor, did not reverse the anticonvulsant effect, demonstrating that 4TRP does not bind to the benzodiazepine-binding site. Furthermore, 4TRP decreased the sodium current through voltage-dependent sodium channels, and thus its anticonvulsant effect may be related to changes in neuronal excitability because of modulation of these channels.

scholarly journals K+ channel blockade in the NTS alters efficacy of two cardiorespiratory reflexes in vivo

1998 ◽  
Vol 274 (3) ◽  
pp. R677-R685 ◽  
Author(s):  
James W. Butcher ◽  
Julian F. R. Paton
Keyword(s):  
Potassium Channel ◽  
Neuronal Excitability ◽  
Baroreceptor Reflex ◽  
Right Atrial ◽  
K Channel ◽  
Reflex Bradycardia ◽  
Potassium Conductances ◽  
Voltage Dependent

We investigated the role of potassium conductances in the nucleus of the solitary tract (NTS) in determining the efficacy of the baroreceptor and cardiopulmonary reflexes in anesthetized rats. The baroreceptor reflex was elicited with an intravenous injection of phenylephrine to evoke a reflex bradycardia, and the cardiopulmonary reflex was evoked with a right atrial injection of phenylbiguanide. Microinjection of two Ca-dependent potassium channel antagonists (apamin and charybdotoxin) into the NTS potentiated the baroreceptor reflex bradycardia. This may reflect the increased neuronal excitability observed previously in vitro with these blockers. In contrast, the Ca-dependent potassium channel antagonists attenuated the cardiopulmonary reflex, whereas voltage-dependent potassium channel antagonists (4-aminopyridine and dendrotoxin) attenuated both the baro- and cardiopulmonary reflexes when microinjected into the NTS. The possibility that the reflex attenuation observed indicates a predominant distribution of certain potassium channels on γ-aminobutyric acid interneurons is discussed.

The development of voltege-dependent ionic conductances In murine spinal cord neurones in culture

1988 ◽  
Vol 66 (10) ◽  
pp. 1328-1336 ◽  
Author(s):  
C. Krieger ◽  
T. A. Sears
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Potassium Conductance ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Calcium Dependent ◽  
Ionic Conductances ◽  
Voltage Dependent

The development of voltage-dependent ionic conductances of foetal mouse spinal cord neurones was examined using the whole-cell patch-clamp technique on neurones cultured from embryos aged 10–12 days (E10–E12) which were studied between the first day in vitro (V1) to V10. A delayed rectifier potassium conductance (IK) and a leak conductance were observed in neurones of E10.V1, E11, V1, and E12, V1 as well as in neurones cultured for longer periods. A rapidly activating and inactivating potassium conductance (IA) was seen in neurones from E11, V2 and E12, V1 and at longer times in vitro. A tetrodotoxin (TTX) sensitive sodium-dependent inward current was observed in neurones of E11 and E12 from V1 onwards. Calcium-dependent conductances were not detectable in these neurones unless the external calcium concentration was raised 10- to 20-foid and potassium conductances were blocked. Under these conditions calcium currents could be observed as early as E11, V3 and E12, V2 and at subsequent times in vitro. The pattern of development of voltage-dependent ionic conductances in murine spinal neurones is such that initially leak and potassium currents are present followed by sodium current and subsequently calcium current.

scholarly journals Contribution of near-threshold currents to intrinsic oscillatory activity in rat medial entorhinal cortex layer II stellate cells

2013 ◽  
Vol 109 (2) ◽  
pp. 445-463 ◽  
Author(s):  
Anne Boehlen ◽  
Christian Henneberger ◽  
Uwe Heinemann ◽  
Irina Erchova
Keyword(s):  
Entorhinal Cortex ◽  
Neuronal Excitability ◽  
Spatial Information ◽  
Sodium Current ◽  
Stellate Cells ◽  
Frequency Component ◽  
Oscillatory Activity ◽  
Potential Oscillations ◽  
Near Threshold

The temporal lobe is well known for its oscillatory activity associated with exploration, navigation, and learning. Intrinsic membrane potential oscillations (MPOs) and resonance of stellate cells (SCs) in layer II of the entorhinal cortex are thought to contribute to network oscillations and thereby to the encoding of spatial information. Generation of both MPOs and resonance relies on the expression of specific voltage-dependent ion currents such as the hyperpolarization-activated cation current ( IH), the persistent sodium current ( INaP), and the noninactivating muscarine-modulated potassium current ( IM). However, the differential contributions of these currents remain a matter of debate. We therefore examined how they modify neuronal excitability near threshold and generation of near-threshold MPOs and resonance in vitro. We found that resonance mainly relied on IH and was reduced by IH blockers and modulated by cAMP and an IM enhancer but that neither of the currents exhibited full control over MPOs in these cells. As previously reported, IH controlled a theta-frequency component of MPOs such that blockade of IH resulted in fewer regular oscillations that retained low-frequency components and high peak amplitude. However, pharmacological inhibition and augmentation of IM also affected MPO frequencies and amplitudes. In contrast to other cell types, inhibition of INaP did not result in suppression of MPOs but only in a moderation of their properties. We reproduced the experimentally observed effects in a single-compartment stochastic model of SCs, providing further insight into the interactions between different ionic conductances.

scholarly journals Up-Regulation of A-Type Potassium Currents Protects Neurons Against Cerebral Ischemia

2011 ◽  
Vol 31 (9) ◽  
pp. 1823-1835 ◽  
Author(s):  
Ping Deng ◽  
Zhi-Ping Pang ◽  
Zhigang Lei ◽  
Sojin Shikano ◽  
Qiaojie Xiong ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Recombinant Expression ◽  
Potassium Currents ◽  
Protective Role ◽  
Pathological Process ◽  
Voltage Dependent ◽  
Protein Kinase Cα ◽  
Excitotoxic Cell Death

Excitotoxicity is the major cause of many neurologic disorders including stroke. Potassium currents modulate neuronal excitability and therefore influence the pathological process. A-type potassium current ( IA) is one of the major voltage-dependent potassium currents, yet its roles in excitotoxic cell death are not well understood. We report that, following ischemic insults, the IA increases significantly in large aspiny (LA) neurons but not medium spiny (MS) neurons in the striatum, which correlates with the higher resistance of LA neurons to ischemia. Activation of protein kinase Cα increases IA in LA neurons after ischemia. Cultured neurons from transgenic mice lacking both Kv1.4 and Kv4.2 subunits exhibit an increased vulnerability to ischemic insults. Increase of IA by recombinant expression of Kv1.4 or Kv4.2 is sufficient in improving the survival of MS neurons against ischemic insults both in vitro and in vivo. These results, taken together, provide compelling evidence for a protective role of IA against ischemia.

scholarly journals Ps in the (Channel) Pod Are Not Alike …

2007 ◽  
Vol 7 (5) ◽  
pp. 136-137
Author(s):  
Yoav Noam ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Phosphorylation Sites ◽  
Voltage Dependent ◽  
Activity Dependent ◽  
Stimulation Of ◽  
Cultured Hippocampal Neurons

Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

scholarly journals Sodium Along With Low-Threshold Potassium Currents Enhance Coincidence Detection of Subthreshold Noisy Signals in MSO Neurons

2004 ◽  
Vol 91 (6) ◽  
pp. 2465-2473 ◽  
Author(s):  
Gytis Svirskis ◽  
Vibhakar Kotak ◽  
Dan H. Sanes ◽  
John Rinzel
Keyword(s):  
Sodium Current ◽  
Sodium Concentration ◽  
Coincidence Detection ◽  
Reverse Correlation ◽  
Spike Generation ◽  
Voltage Dependent ◽  
Two Factors ◽  
Noisy Signals ◽  
Low Threshold

Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels ( IKLT) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an IKLT antagonist. These observations suggest that the sodium current ( INa) was substantially inactivated at rest. To test this idea, INa was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of INa nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT showed reduction in coincidence detection when IKLT was reduced or when INa was increased. We hypothesize that desirable synaptic signals first remove some inactivation of INa and reduce activation of IKLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.

scholarly journals Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4761
Author(s):  
Wei Hu ◽  
Robert B. Clark ◽  
Wayne R. Giles ◽  
Erwin Shibata ◽  
Henggui Zhang
Keyword(s):  
Adult Mouse ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Mouse Heart ◽  
Voltage Dependent ◽  
Electrophysiological Studies ◽  
Ionic Mechanisms ◽  
K Current ◽  
Significant Expression

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.

Late Sodium Channel Openings Underlying Epileptiform Activity Are Preferentially Diminished by the Anticonvulsant Phenytoin

1997 ◽  
Vol 77 (6) ◽  
pp. 3021-3034 ◽  
Author(s):  
Michael M. Segal ◽  
Andrea F. Douglas
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Hippocampal Neurons ◽  
Sodium Current ◽  
Epileptiform Activity ◽  
Normal Function ◽  
Anticonvulsant Effect ◽  
Persistent Sodium Current ◽  
Pharmacological Mechanism ◽  
Voltage Dependent

Segal, Michael M. and Andrea F. Douglas. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J. Neurophysiol. 77: 3021–3034, 1997. Late openings of sodium channels were observed in outside-out patch recordings from hippocampal neurons in culture. In previous studies of such neurons, a persistent sodium current appeared to underlie the ictal epileptiform activity. All the channel currents were blocked by tetrodotoxin. In addition to the transient openings of sodium channels making up the peak sodium current, there were two types of late channel openings: brief late and burst openings. These late channel openings occurred throughout voltage pulses that lasted 750 ms, producing a persistent sodium current. At −30 mV, this current was 0.4% of the peak current. The late channel openings occurred throughout the physiological range of trans-membrane voltages. The anticonvulsant phenytoin reduced the late channel openings more than the peak currents. The effect on the persistent current was greatest at more depolarized voltages, whereas the effect on peak currents was not substantially voltage dependent. In the presence of 60 μM phenytoin, peak sodium currents at −30 mV were 40–41% of control, as calculated using different methods of analysis. Late currents were 22–24% of control. Phenytoin primarily decreased the number of channel openings, with less effect on the duration of channel openings and no effect on open channel current. This set of findings is consistent with models in which phenytoin binds to the inactivated state of the channel. The preferential effect of phenytoin on the persistent sodium current suggests that an important pharmacological mechanism for a sodium channel anticonvulsant is to reduce late openings of sodium channels, rather than reducing all sodium channel openings. We hypothesize that pharmacological interventions that are most selective in reducing late openings of sodium channels, while leaving early channel openings relatively intact, will be those that produce an anticonvulsant effect while interfering minimally with normal function.

Induction of voltage-dependent sodium channels by in vitro differentiation of human retinoblastoma cells

1993 ◽  
Vol 70 (4) ◽  
pp. 1487-1496 ◽  
Author(s):  
M. del Pilar Gomez ◽  
G. Waloga ◽  
E. Nasi
Keyword(s):  
Sodium Current ◽  
Inactivation Kinetics ◽  
Bathing Solution ◽  
Inactivation Curve ◽  
Inward Current ◽  
Differentiated Cells ◽  
Sodium Removal ◽  
Voltage Dependent ◽  
Undifferentiated Cells

1. Neuronlike differentiation of Y-79 retinoblastoma was chemically induced in vitro, by plating the cells onto a poly-D-lysine and laminin substrate. The changes in voltage-dependent conductances after 48-72 h were examined with the whole-cell tight-seal and the perforated-patch recording techniques. 2. Although outward currents carried by potassium ions appeared qualitatively similar before and after differentiation, the depolarization-activated transient inward current displayed a pronounced acceleration of its activation and inactivation kinetics. 3. After differentiation, both the threshold of activation and the steady-state inactivation curve of the inward current are displaced in the negative direction by approximately 10-20 mV as compared with untreated cells. The current attains its peak amplitude in approximately 1 ms at maximum activating voltages, and decays within 3 ms. In contrast, in undifferentiated cells these values are on the order of 6 and 60 ms, respectively. The time to recover from inactivation is also shortened 20-fold in differentiated cells. 4. Unlike the mixed conductance of undifferentiated cells, which requires extracellular calcium, the inward current of the neuronlike differentiated cells is insensitive to manipulations of external calcium. Instead, it can be completely abolished in a reversible way by sodium removal or by micromolar concentrations of tetrodotoxin (TTX) in the bathing solution. As such, it resembles in all salient respects the voltage-dependent sodium conductance of nerve cells. 5. The fast sodium current expressed after neuronal differentiation is not the result of a progressive enhancement of an existing conductance, because no such component is discernible in undifferentiated cells. Moreover, recordings performed in cells at early stages of differentiation also failed to reveal the coexistence of the immature and the differentiated inward currents. 6. A possible account of the present observations is that the native inward current of undifferentiated Y-79 cells may correspond to a precursor form of the mature channel, and the observed developmental changes induced by chemical differentiation could be a consequence of progressive modification of the original channels, rather than expression of a separate class of proteins.

Altered PKA modulation in the Nav1.1 epilepsy variant I1656M

2013 ◽  
Vol 110 (9) ◽  
pp. 2090-2098 ◽  
Author(s):  
Shuai Liu ◽  
Ping Zheng
Keyword(s):  
Protein Kinases ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Febrile Seizures ◽  
Patch Clamp Technique ◽  
Gene Encoding ◽  
Α Subunit ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Febrile Seizures Plus

Genetic epilepsy with febrile seizures plus (GEFS+) is an inherited epilepsy that can result from mutations in at least four ion channel subunits. The majority of the known GEFS+ mutations have been identified in SCN1A, the gene encoding Nav1.1 α-subunit. Protein kinases as critical modulators of sodium channels have been closely related to the genesis of epilepsy. However, little is known about how protein kinases affect the GEFS+ mutant sodium channel. To gain insight into the protein kinases effect on channel properties and neuronal excitability of SCN1A mutant channels, we investigated the human SCN1A GEFS+ mutation I1656M by using whole cell patch-clamp technique and an established computational neuron model. The results showed that the PKA inhibition of sodium current amplitude significantly decreased in the I1656M mutant channels, but the PKC inhibition did not. The responses of the voltage-dependent activation and fast inactivation to PKA activator disappeared in the I1656M mutant channels, but the response of the voltage dependence of the slow inactivation did not. Computational model analysis suggested that changes of the I1656M mutant channel gating behaviors in response to PKA activation altered neuronal excitability. These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability.

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