Membrane Excitability Of Neurons Research Articles

Electrolytes Disturbances and Seizures

Electrolytes Disturbances and Seizures

Excitability of the human epileptic cortex after chronic valproate: A reappraisal

We explored the action of chronic valproic acid (VPA) on the human epileptic cortex by means of transcranial magnetic stimulation (TMS). TMS is an emerging biomarker for neurotropic drugs. We had 15 drug-naive patients with different epileptic syndromes. Interictally, we measured several TMS indexes of cortical excitability before commencing VPA and 3 months later. At that time, all patients were clinical responders to the drug, whose plasma levels were in the “therapeutic range”. We then compared the two conditions, while 18 healthy subjects, of whom 12 were retested at a similar delay, acted as controls. In the pooled patients, the baseline resting motor threshold to TMS was similar to that of controls, but it increased significantly ( P < 0.05) after VPA. Intracortical facilitation, another index of cortical excitability, was abnormally enhanced at baseline but decreased significantly after VPA ( P < 0.05). On splitting patients according to their diagnosis, the threshold increase was significant ( P < 0.05) among partial, but not generalized epilepsies. The reverse was true for changes in intracortical facilitation. TMS phenomena had no linear relation to VPA serum levels. Based on the known pharmacology of TMS effects, VPA reduced the intrinsic membrane excitability of motor cortical neurons, possibly through changes in Na+ channel activity. Then, VPA corrected a transmitter-mediated interneuronal hyper-excitability of the primary motor cortex. The former effect was best seen in partial, and the latter in generalized epilepsy patients.

Interactions between GABA-B 1 receptors and Kir 3 inwardly rectifying potassium channels

γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts via both ionotropic GABA-A and metabotropic GABA-B receptors. We evaluated the interaction of receptors with members of the inwardly rectifying potassium (Kir 3) channel family, which also play an important role in neuronal transmission and membrane excitability. These channels are functionally regulated by GABA-B receptors. Possible physical interactions between GABA-B receptor and Kir 3 channels expressed in HEK cells were evaluated using Bioluminescence Resonance Energy Transfer (BRET) experiments, co-immunoprecipitation and confocal microscopy. Our data indicate that Kir 3 channels and Gβγ subunits can interact with the GABA-B 1 subunits independently of the GABA-B 2 subunit or Kir 3.4 which are ultimately responsible for their targetting to the cell surface. Thus signalling complexes containing GABA-B receptors, G proteins and Kir channels are formed shortly after biosynthesis most likely in the endoplasmic reticulum.

Participation of sodium currents in burst generation and control of membrane excitability in mesencephalic trigeminal neurons.

Subthreshold sodium currents are important in sculpting neuronal discharge and have been implicated in production and/or maintenance of subthreshold membrane oscillations and burst generation in mesencephalic trigeminal neurons (Mes V). Moreover, recent data suggest that, in some CNS neurons, resurgent sodium currents contribute to production of high-frequency burst discharge. In the present study, we sought to determine more directly the participation of these currents during Mes V electrogenesis using the action potential-clamp method. In postnatal day 8-14 rats, the whole-cell patch-clamp method was used to record sodium currents by subtraction in response to application of TTX in voltage-clamp mode using the action potential waveform as the command protocol. We found that TTX-sensitive sodium current is the main inward current flowing during the interspike interval, compared with the h-current (Ih) and calcium currents. Furthermore, in addition to the transient sodium current that flows during the upstroke of action potential, we show that resurgent sodium current flows at the peak of afterhyperpolarization and persistent sodium current flows in the middle of the interspike interval to drive high-frequency firing. Additionally, transient, resurgent, and persistent sodium current components showed voltage- and time-dependent slow inactivation, suggesting that slow inactivation of these currents can contribute to burst termination. The data suggest an important role for these components of the sodium current in Mes V neuron electrogenesis.

Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex.

The entorhinal cortex (EC) is a significant component of the systems that underlie certain forms of memory formation and recall. Evidence has been emerging that the dopaminergic system in the EC facilitates these and other functions of the EC. The effects of dopamine (DA) on membrane properties and excitability of EC neurons, however, are not known. We used in vitro whole-cell patch-clamp recordings from layer V pyramidal neuronal somata and dendrites of the adult rat lateral EC to investigate the effects of DA on the excitability of these neurons. We found that brief application of DA caused a reduction in the excitability of layer V EC pyramidal neurons. This effect was attributable to voltage-dependent modification of membrane properties that can best be explained by an increase in a hyperpolarization-activated conductance. Furthermore, the effects of DA were blocked by pharmacological blockade of h-channels, but not by any of a number of other ion channels. These actions were produced by a D1 receptor-mediated increase of cAMP but were independent of protein kinase A. A portion of the actions of DA can be attributed to effects in the apical dendrites. The data suggest that DA can directly influence the membrane properties of layer V EC pyramidal neurons by modulation of h-channels. These actions may underlie some of the effects of DA on memory formation.

Relationship Between Migraine and Epilepsy in Pediatric Age

Many studies have supported the hypothesis of alteration of cortical hyperexcitability as a possible pathological mechanism underlying the onset of migraine and epileptic attacks. Different biochemical pathways involving cellular structures may increase or decrease the excitability of neuronal membranes. The aim of this study was to identify a possible link between migraine and epilepsy from a clinical and neurophysiologic point of view. One-hundred thirty-seven children and adolescents consecutively diagnosed for tension-type headache and idiopathic migraine with and without aura were studied. Anamnestic, clinical, and instrumental data were collected by a neurological examination, a specific questionnaire, and awake electroencephalogram (EEG) registrations. EEG features of nonheadache and nonseizures control group were compared. Fourteen cases (10.2%) had a positive history for seizures with fever, isolated seizures, or epilepsy. Distribution differed according to headache diagnosis; migraine with aura (MWA) was largely prevalent. Specific electroencephalographic abnormalities were present in 11.7% of the sample, with a significant different distribution across the groups of children with headache and the control group: specific interictal abnormalities were found in 10 of 23 (43.5%) children with MWA. Two factors, seizures and specific interictal electroencephalographic abnormalities, showed a different distribution in patients with MWA compared to other classes of headache and control group (P < or = .01). The present study supports the hypothesis of a possible clinical continuum between some types of MWA and epileptic syndromes as entities due to altered neuronal excitability with similar genetic substrates.

Neuropathology in Drosophila Membrane Excitability Mutants

Mutations affecting ion channels and neuronal membrane excitability have been identified in Drosophila as well as in other organisms and characterized for their acute effects on behavior and neuronal function. However, the long-term effect of these perturbations on the maintenance of neuronal viability has not been studied in detail. Here we perform an initial survey of mutations affecting Na+ channels and K+ channels in Drosophila to investigate their effects on life span and neuronal viability as a function of age. We find that mutations that decrease membrane excitability as well as those that increase excitability can trigger neurodegeneration to varying degrees. Results of double-mutant interactions with dominant Na+/K+ ATPase mutations, which themselves cause severe neurodegeneration, suggest that excitotoxicity owing to hyperexcitability is insufficient to explain the resultant phenotype. Although the exact mechanisms remain unclear, our results suggest that there is an important link between maintenance of proper neuronal signaling and maintenance of long-term neuronal viability. Disruption of these signaling mechanisms in any of a variety of ways increases the incidence of neurodegeneration.

The Kv2.1 C Terminus Can Autonomously Transfer Kv2.1-Like Phosphorylation-Dependent Localization, Voltage-Dependent Gating, and Muscarinic Modulation to Diverse Kv Channels

Modulation of K+ channels is widely used to dynamically regulate neuronal membrane excitability. The voltage-gated K+ channel Kv2.1 is an abundant delayed rectifier K+ (IK) channel expressed at high levels in many types of mammalian central neurons where it regulates diverse aspects of membrane excitability. Neuronal Kv2.1 is constitutively phosphorylated, localized in high-density somatodendritic clusters, and has a relatively depolarized voltage dependence of activation. Here, we show that the clustering and voltage-dependent gating of endogenous Kv2.1 in cultured rat hippocampal neurons are modulated by cholinergic stimulation, a common form of neuromodulation. The properties of neuronal Kv2.1 are recapitulated in recombinant Kv2.1 expressed in human embryonic kidney 293 (HEK293) cells, but not COS-1 cells, because of cell background-specific differences in Kv2.1 phosphorylation. As in neurons, Kv2.1 in HEK293 cells is dynamically regulated by cholinergic stimulation, which leads to Ca2+/calcineurin-dependent dephosphorylation of Kv2.1, dispersion of channel clusters, and hyperpolarizing shifts in the voltage-dependent gating properties of the channel. Immunocytochemical, biochemical, and biophysical analyses of chimeric Kv channels show that the Kv2.1 cytoplasmic C-terminal domain can act as an autonomous domain sufficient to transfer Kv2.1-like clustering, voltage-dependent activation, and cholinergic modulation to diverse Kv channels. These findings provide novel mechanistic insights into cholinergic modulation of ion channels and regulation of the localization and voltage-dependent gating properties of the abundant neuronal Kv2.1 channel by cholinergic and other neuromodulatory stimuli.

Hyperexcitability of Axotomized and Neighboring Unaxotomized Sensory Neurons Is Reduced Days After Perineural Clonidine at the Site of Injury

Hyperexcitability after peripheral nerve injury occurs in axotomized and neighboring unaxotomized dorsal root ganglion (DRG) neurons and contributes to hypersensitivity. Previous studies have focused on proximal nerve injury and have not examined unaxotomized neurons innervating the site of sensory testing. The current study used a distal nerve injury (partial sciatic nerve ligation [PSNL]), and identified, using fluorescent tracers, axotomized and unaxotomized neurons innervating the site of hypersensitivity. We hypothesized that reduced hypersensitivity after perineural clonidine was associated with reduced hyperexcitability of DRG neurons. Rats underwent sham or PSNL surgery, followed 2 wk later by a single injection at the injury site of clonidine or saline. PSNL, but not sham surgery, reduced hindpaw mechanical withdrawal threshold, and clonidine, but not saline, partially reversed this effect 3 days after injection. Intracellular recording of neurons in whole DRG demonstrated similar changes in membrane properties and excitability in unaxotomized and axotomized neurons after PSNL compared with sham surgery, primarily depolarized resting membrane potential, reduced rheobase, presence of oscillations, and capability to fire repetitively. Most of these changes were present in small-, medium-, and large-diameter neurons. Perineural clonidine 3 days later significantly reversed many of these effects, whereas saline was without effect. We speculate that perineural clonidine reduces signals, likely proinflammatory cytokines and prostaglandins produced during Wallerian degeneration after nerve injury, which drive changes in ion channel expression in DRG somata leading to hyperexcitability and hypersensitivity.

Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability

KCNQ2 and KCNQ3 ion channel pore-forming subunits coassemble to form a heteromeric voltage-gated potassium channel that underlies the neuronal M-current. We and others showed that calmodulin (CaM) binds to specific sequence motifs in the C-terminal domain of KCNQ2 and KCNQ3. We also found that a fusion protein containing a KCNQ2 CaM-binding motif, coexpressed with KCNQ2 and KCNQ3, competes with the full-length KCNQ2 channel for CaM binding and thereby decreases KCNQ2/3 current density in heterologous cells. We have explored the importance of CaM binding for the generation of the native M-current and regulation of membrane excitability in rat hippocampal neurons in primary cell culture. M-current properties were studied in cultured neurons by using whole-cell patch clamp recording. The M-current density is lower in neurons expressing the CaM-binding motif fusion protein, as compared to control neurons transfected with vector alone. In contrast, no change in M-current density is observed in cells transfected with a mutant fusion protein that is unable to bind CaM. The CaM-binding fusion protein does not influence the rapidly inactivating A-current or the large conductance calcium-activated potassium channel-mediated fast spike afterhyperpolarization in neurons in which the M-current is suppressed. Furthermore, the CaM-binding fusion protein, but not the nonbinding mutant, increases both the number of action potentials evoked by membrane depolarization and the size of the spike afterdepolarization. These results suggest that CaM binding regulates M-channel function and membrane excitability in the native neuronal environment.

Long-term synaptic facilitation in defensive behavior command neurons in the snail during acquisition of sensitization depends on RNA synthesis

Experiments on defensive behavior command neuron LP11 in semi-intact common snails preparations were performed to study transcription processes underlying the mechanisms of neuronal plasticity during acquisition of nociceptive sensitization. Application of nociceptive stimuli to the heads of control snails led to increases in neuron membrane excitability, along with biphasic changes in responses to tactile and chemical sensory stimulation--with depressed responses at the short-term stage and facilitation in the long-term stage of sensitization. Acquisition of sensitization after application of the RNA synthesis inhibitor actinomycin D (20 microM) to neuron LP11 led to complete suppression of synaptic facilitation in responses to sensory stimulation in the long-term stage of sensitization, but had no effect on the short-term depression of responses. However, the inhibitor had no effect on changes in membrane excitability in these conditions. Application of actinomycin D 30 min after the end of the sensitization acquisition process (1 h after the process started) had no effect on membrane excitability or synaptic facilitation. It is suggested that the induction of long-term synaptic facilitation in neuron LP11 during acquisition of nociceptive sensitization is dependent on RNA synthesis occurring in a narrow time interval, while changes in membrane excitability during the 2-3 h after acquisition of sensitization and short-term synaptic plasticity are independent of transcription processes.

Modulation of Spontaneous Firing in Rat Subthalamic Neurons by 5-HT Receptor Subtypes

The subthalamic nucleus (STN) is considered to be one of the driving forces in the basal ganglia circuit. The STN is innervated by serotonergic afferents from the raphe nucleus and expresses a variety of 5-HT receptor subtypes. We investigated the effects of 5-HT and 5-HT receptor subtype agonists and antagonists on the firing properties of STN neurons in rat brain slices. We used cell-attached, perforated-patch, and whole cell recording techniques to detect changes in firing frequency and pattern and electrical membrane properties. Due to the depolarization of membrane potential caused by reduced potassium conductance, 5-HT (10 microM) increased the firing frequency of STN neurons without changing their firing pattern. Cadmium failed to occlude the effect of 5-HT on firing frequency. 5-HT had no effect on afterhyperpolarization current. These results indicated that the 5-HT action was not mediated by high-voltage-activated calcium channel currents and calcium-dependent potassium currents. 5-HT had no effect on hyperpolarization-activated cation current (I(H)) amplitude and voltage-dependence of I(H) activation, suggesting that I(H) was not involved in 5-HT-induced excitation. The increased firing by 5-HT was mimicked by 5-HT(2/4) receptor agonist alpha-methyl-5-HT and was partially mimicked by 5-HT2 receptor agonist DOI or 5-HT4 receptor agonist cisapride. The 5-HT action was partially reversed by 5-HT4 receptor antagonist SB 23597-190, 5-HT2 receptor antagonist ketanserin, and 5-HT2C receptor antagonist RS 102221. Our data indicate that 5-HT has significant ability to modulate membrane excitability in STN neurons; modulation is accomplished by decreasing potassium conductance by activating 5-HT4 and 5-HT2C receptors.

Cocaine-Induced Plasticity of Intrinsic Membrane Properties in Prefrontal Cortex Pyramidal Neurons: Adaptations in Potassium Currents

Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC. This long-lasting, cocaine-induced plasticity of membrane excitability in PFC pyramidal neurons may contribute to the impaired decision making and drug craving that characterize cocaine withdrawal.

17β-estradiol inhibits outward potassium currents recorded in rat parabrachial nucleus cells in vitro

Evidence is increasingly accumulating in support of a role for the steroid hormone 17β-estradiol to modify neuronal functions in the mammalian CNS, especially in autonomic centers. In addition to its well known slowly developing and long lasting actions (genomic), estrogen can also rapidly modulate cell signaling events by affecting membrane excitability (non-genomic). Little, however, is known regarding the mechanism(s) by which 17β-estradiol produces its rapid effects on neuronal membrane excitability. As potassium channels play a crucial role in cell excitability, we hypothesized that 17β-estradiol caused excitability by modulating potassium flux through the neuronal cell membrane. We tested this hypothesis by examining the effects of 17β-estradiol on outward potassium currents recorded in cells from the parabrachial nucleus of rats, in vitro. Bath application of 17β-estradiol (10–100μM) reversibly reduced voltage-activated outward potassium currents in a concentration-dependent manner. This effect was mimicked by BSA-17β-estradiol but not mimicked by 17α-estradiol and was significantly reduced by ICI 182,780, a selective estrogen receptor antagonist. The inhibitory effect of 17β-estradiol was dependent on extracellular potassium concentration, with more profound effects observed at lower concentrations. The 17β-estradiol-induced inhibition of the outward current was blocked by pretreatment with the potassium channel blockers tetraethylammonium and 4-aminopyridine. The time constants of deactivation of tail currents were decreased by 17β-estradiol over a range of test potentials (−140 to −80 mV). Finally, the inhibitory effect of 17β-estradiol on the outward potassium currents was blocked following pre-incubation of slices in lavendustin A, a tyrosine kinase inhibitor. Taken together, these results suggest that 17β-estradiol acts rapidly at an extracellular membrane receptor to reduce tetraethylammonium- and 4-aminopyridine-sensitive outward potassium currents by accelerating the closure of potassium channels. This may be the ionic basis of 17β-estradiol-induced enhancement of neuronal excitability.

Persistent Sodium Currents in Mesencephalic V Neurons Participate in Burst Generation and Control of Membrane Excitability

The functional and biophysical properties of a persistent sodium current (I(NaP)) previously proposed to participate in the generation of subthreshold oscillations and burst discharge in mesencephalic trigeminal sensory neurons (Mes V) were investigated in brain stem slices (rats, p7-p12) using whole cell patch-clamp methods. I(NaP) activated around -76 mV and peaked at -48 mV, with V1/2 of -58.7 mV. Ramp voltage-clamp protocols showed that I(NaP) undergoes time- as well as voltage-dependent inactivation and recovery from inactivation in the range of several seconds (tau(onset) = 2.04 s, tau(recov) = 2.21 s). Riluzole (< or =5 microM) substantially reduced I(NaP), membrane resonance, postinhibitory rebound (PIR), and subthreshold oscillations, and completely blocked bursting, but produced modest effects on the fast transient Na+ current (I(NaT)). Before complete cessation, burst cycle duration was increased substantially, while modest and inconsistent changes in burst duration were observed. The properties of the I(NaT) were obtained and revealed that the amplitude and voltage dependence of the resulting "window current" were not consistent with those of the observed I(NaP) recorded in the same neurons. This suggests an additional mechanism for the origin of I(NaP). A neuronal model was constructed using Hodgkin-Huxley parameters obtained experimentally for Na+ and K+ currents that simulated the experimentally observed membrane resonance, subthreshold oscillations, bursting, and PIR. Alterations in the model g(NaP) parameters indicate that I(NaP) is critical for control of subthreshold and suprathreshold Mes V neuron membrane excitability and burst generation.

Repeated Cocaine Administration Increases Membrane Excitability of Pyramidal Neurons in the Rat Medial Prefrontal Cortex

Although the medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction, the effects of chronic cocaine on mPFC neurons remain poorly understood. Here, we performed visualized current-clamp recordings to determine the effects of repeated cocaine administration on the membrane excitability of mPFC pyramidal neurons in rat brain slices. Following repeated cocaine administration (15 mg/kg/day i.p. for 5 days) with a 3-day withdrawal, alterations in membrane properties, including increased input resistance, reduced intensity of intracellular injected currents required for generation of Na(+)-dependent spikes (rheobase), and an increased number of spikes evoked by depolarizing current pulses were observed in mPFC neurons. The current-voltage relationship was also altered in cocaine-pretreated neurons showing reduced outward rectification during membrane depolarization and decreased inward rectification during membrane hyperpolarization. Application of the K(+) channel blocker Ba(2+) depolarized the resting membrane potential (RMP) and enhanced membrane potential response to injection of hyperpolarizing current pulses. However, the effects of Ba(2+) on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells. These findings indicate that repeated cocaine administration increased the excitability of mPFC neurons after a short-term withdrawal, possibly via reducing the activity of the potassium inward rectifiers (K(ir)) and voltage-gated K(+) currents. Similar changes were also observed in cocaine-pretreated mPFC neurons after a long-term (2-3 weeks) withdrawal, revealing a persistent increase in excitability. These alterations in mPFC neuronal excitability may contribute to the development of behavioral sensitization and withdrawal effects following chronic cocaine exposure.

Developmental changes of transient potassium currents in large aspiny neurons in the neostriatum

Developmental regulation of the potassium conductance is important for the maturation of neuronal excitability and the formation of functional circuitry in the central nervous system (CNS). The rapidly inactivating A-type current is a major component of the voltage-dependent outward potassium currents in the large aspiny (LA) neurons in the neostriatum. The large aspiny neurons play important roles in the function of neostriatum in physiological and pathological conditions. Whole-cell patch-clamp recording was performed on acutely dissociated neurons and brain slices to investigate the postnatal development of A-type current in the large aspiny neurons. The current density of A-type current in large aspiny neurons was the highest at postnatal 1–3 days and gradually decreased during the development with the lowest levels in adult animals. In comparison to postnatal 1–3 days, the steady-state inactivation curve shifted in depolarizing direction in mature neurons. No significant changes in the voltage dependence of steady-state activation were observed during development. Consistent with the decrease in the current density of A-type current during development, the latency to the first spike was dramatically shortened in mature large aspiny neurons. These results suggest that the decrease of rapidly inactivating A-type potassium current during development might contribute, at least in part, to the maturation of the membrane excitability of large aspiny neurons in the neostriatum.

Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity

ATP-sensitive K+ (KATP) channels play many important roles in cellular functions, including control of membrane excitability of skeletal muscle and neurons, K+ recycling in renal epithelia, cytoprotection in cardiac ischemia, and insulin secretion from pancreatic β-cells. KATP channels are composed of pore-forming inwardly rectifying potassium channel (Kir6.2 or Kir6.1) subunits and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Kir6.2 or Kir6.1 subunits conjoined with a SUR subunit constitute the various tissue-specific KATP channels with distinct pharmacological properties. Both sulfonylureas and non-sulfonylurea hypoglycemic agents are used in treatment of type 2 diabetes mellitus. While the sulfonylurea receptor (SUR) is the target molecule of all of these hypoglycemic agents, the binding sites differ according to the moiety containing in the agent, and alter the pharmachological properties. In addition, chronic exposure of pancreatic β-cells to the various agents affects the agent-specific sensitivities differently.Here we distinguish differences in pharmacological profile among the various hypoglycemic agents that reflect their chemical composition. We also suggest possible risk in the use of certain hypoglycemic agents in patients with ischemic heart disease.

The selective effect of a protein kinase C inhibitor on synaptic plasticity in defensive behavior command neurons during development of sensitization in the snail.

Studies of defensive behavior command neurons LP11 and RP11 in semi-intact common snail preparations addressed the effects of the protein kinase C antagonist polymyxin B on the effect of nociceptive sensitization. Neurons in control snails responded to application of nociceptive stimuli to the head with membrane depolarization, increases in excitability, and depression of neuron responses to sensory stimulation during the short-term stage, with marked facilitation of responses during the long-term stage of sensitization. Acquisition of sensitization in the presence of polymyxin B resulted in partial suppression of responses to nociceptive stimuli. Changes in command neuron membrane excitability in these conditions, as well as changes in responses to tactile stimulation of the foot and chemical stimulation of the head, were similar to those seen in neurons of sensitized control animals. The inhibitor also had no effect on short-term depression of neuron responses induced by tactile stimulation of the head. In addition, acquisition of sensitization during administration of polymyxin B led to complete suppression of the facilitation of responses to tactile stimulation of the snail's head during the long-term stage of sensitization. It is suggested that in sensitized common snails, protein kinase C is involved in controlling the mechanisms of nociception and is also involved in the mechanisms of selective induction of plasticity in the synaptic inputs of command neurons, which are activated by tactile stimulation of the animal's head.

Matching molecules to function: neuronal Ca 2+-activated K + channels and afterhyperpolarizations

Potassium channels regulate the membrane excitability of neurons, play a major role in shaping action potentials, determining firing patterns and regulating neurotransmitter release, and thus significantly contribute to neuronal signal encoding and integration. This review focuses on the molecular and cellular basis for the specific function of small-conductance calcium-activated potassium channels (SK channels) in the nervous system. SK channels are activated by an intracellular increase of free calcium during action potentials. They mediate currents that modulate the firing frequency of neurons. Three SK channel subunits have been cloned and form channels, which are voltage-insensitive, activated by submicromolar intracellular calcium concentrations, and are blocked, with different affinities, by a number of toxins and organic compounds. Different neurons in the central and peripheral nervous system express distinct subsets of SK channel subunits. Recent progress has been made in relating cloned SK channels to their native counterparts. These findings argue in favour of regulatory mechanisms conferring to native SK channels with specific subunit compositions distinct and specific functional profiles in different neurons.