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PubMed2000

Tonic blocking action of meperidine on Na+ and K+ channels in amphibian peripheral nerves.

BACKGROUND: Among opioids, meperidine (pethidine) also shows local anesthetic activity when applied locally to peripheral nerve fibers and has been used for this effect in the clinical setting for regional anesthesia. This study investigated the blocking effects of meperidine on different ion channels in peripheral nerves. METHODS: Experiments were conducted using the outside-out configuration of the patch-clamp method applied to enzymatically prepared peripheral nerve fibers of Xenopus laevis. Half-maximal inhibiting concentrations were determined for Na+ channels and different K+ channels by nonlinear least-squares fitting of concentration-inhibition curves, assuming a one-to-one reaction. RESULTS: Externally applied meperidine reversibly blocked all investigated channels in a concentration-dependent manner, i.e., voltage-activated Na+ channel (half-maximal inhibiting concentration, 164 microM), delayed rectifier K+ channels (half-maximal inhibiting concentration, 194 microM), the calcium-activated K+ channel (half-maximal inhibiting concentration, 161 microM), and the voltage-independent flicker K+ channel (half-maximal inhibiting concentration, 139 microM). Maximal block in high concentrations of meperidine reached 83% for delayed rectifier K+ channels and 100% for all other channels. Meperidine blocks the Na+ channel in the same concentration range as the local anesthetic agent lidocaine (half-maximal inhibiting concentration, 172 microM) but did not compete for the same binding site as evaluated by competition experiments. Low concentrations of meperidine (1 nM to 1 microM) showed no effects on Na+ channels. The blockade of Na+ and delayed rectifier K+ channels could not be antagonized by the addition of naloxone. CONCLUSIONS: It is concluded that meperidine has a nonselective inhibitory action on Na+ and K+ channels of amphibian peripheral nerve. For tonic Na+ channel block, neither an opioid receptor nor the the local anesthetic agent binding site is the target site for meperidine block.

Analgesics, Opioid↗
PubMed1995

An outwardly rectifying K+ current active near resting potential in human retinal pigment epithelial cells.

Currents in freshly dissociated adult human retinal pigment epithelial (RPE) cells were studied using the perforated patch-clamp technique. The zero-current potential (V0) averaged -48.9 +/- 7.7 mV (n = 50). Depolarizing voltage pulses from -70 mV evoked an outward current that activated with first-order kinetics and that did not inactivate during prolonged depolarizations. Repolarizing the membrane potential produced tail currents that reversed near the K+ equilibrium potential, indicating that the sustained outward current was carried mainly by K+. The outwardly rectifying K+ conductance (gK) had an activation threshold voltage near -60 mV and was half-maximal at -37 mV. Approximately 25% of gK was active at the average V0. The K+ current was nearly completely blocked by 2 mM Ba2+ but was relatively insensitive to 20 mM tetraethylammonium. The kinetics, voltage dependence, and blocker sensitivity of this current clearly distinguish it from delayed rectifier K+ currents previously identified in RPE cells. We conclude that the sustained outward K+ current may help establish the resting potential of the apical and/or basolateral membranes and may also participate in K+ transport across the RPE.

Adult↗
PubMed2002

Differential blockade of neuronal voltage-gated Na(+) and K(+) channels by antidepressant drugs.

The effects of a range of antidepressants were investigated on neuronal voltage-gated Na(+) and K(+) channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated 22Na(+) uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na(+) channel. Imipramine also produced a differential action on macroscopic Na(+) and K(+) channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na(+) channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na(+) channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na(+) channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K(+) currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs.

Algorithms↗
PubMed2005

Direct block of cloned hKv1.5 channel by cytochalasins, actin-disrupting agents.

The action of cytochalasins, actin-disrupting agents on human Kv1.5 channel (hKv1.5) stably expressed in Ltk(-) cells was investigated using the whole cell patch-clamp technique. Cytochalasin B inhibited hKv1.5 currents rapidly and reversibly at +60 mV in a concentration-dependent manner with an IC(50) of 4.2 microM. Cytochalasin A, which has a structure very similar to cytochalasin B, inhibited hKv1.5 (IC(50) of 1.4 microM at +60 mV). Pretreatment with other actin filament disruptors cytochalasin D and cytochalasin J, and an actin filament stabilizing agent phalloidin had no effect on the cytochalasin B-induced inhibition of hKv1.5 currents. Cytochalasin B accelerated the decay rate of inactivation for the hKv1.5 currents. Cytochalasin B-induced inhibition of the hKv1.5 channels was voltage dependent with a steep increase over the voltage range of the channel's opening. However, the inhibition exhibited voltage independence over the voltage range in which channels are fully activated. Cytochalasin B produced no significant effect on the steady-state activation or inactivation curves. The rate constants for association and dissociation of cytochalasin B were 3.7 microM/s and 7.5 s(-1), respectively. Cytochalasin B produced a use-dependent inhibition of hKv1.5 current that was consistent with the slow recovery from inactivation in the presence of the drug. Cytochalasin B (10 microM) also inhibited an ultrarapid delayed rectifier K(+) current (I(K,ur)) in human atrial myocytes. These results indicate that cytochalasin B primarily blocks activated hKv1.5 channels and endogenous I(K,ur) in a cytoskeleton-independent manner as an open-channel blocker.

Actins↗
PubMed2000

A DPDPE-induced enhancement of inward rectifier potassium current via opioid receptor in neuroblastomaxglioma NG108-15 cells.

The effect of a delta-selective opioid agonist, DPDPE([D-Pen(2, 5)]-enkephalin), on the inward rectifier potassium current (I(KIR)) of NG108-15 cell was studied by whole cell voltage-clamp technique. It was found that microM DPDPE increased the amplitude and delayed the activation and inactivation of I(KIR) rapidly and reversibly. These effects could be reversed by naloxone, but were still obtained in pertussis toxin (PTX) preincubated cells or when using GDP-betas (guanosine 5'-o-[2-thio] diphoaphate) containing electrodes to block the G-protein coupled events. The above results suggest that DPDPE-induced change of I(KIR) is mediated by delta-opioid receptor but does not involve G-proteins.

Animals↗
PubMed1999

Two types of voltage-gated K(+) currents in dissociated heart ventricular muscle cells of the snail Lymnaea stagnalis.

We have used a combination of current-clamp and voltage-clamp techniques to characterize the electrophysiological properties of enzymatically dissociated Lymnaea heart ventricle cells. Dissociated ventricular muscle cells had average resting membrane potentials of -55 +/- 5 mV. When hyperpolarized to potentials between -70 and -63 mV, ventricle cells were capable of firing repetitive action potentials (8.5 +/- 1.2 spikes/min) that failed to overshoot 0 mV. The action potentials were either simple spikes or more complex spike/plateau events. The latter were always accompanied by strong contractions of the muscle cell. The waveform of the action potentials were shown to be dependent on the presence of extracellular Ca(2+) and K(+) ions. With the use of the single-electrode voltage-clamp technique, two types of voltage-gated K(+) currents were identified that could be separated by differences in their voltage sensitivity and time-dependent kinetics. The first current activated between -50 and -40 mV. It was relatively fast to activate (time-to-peak; 13.7 +/- 0.7 ms at +40 mV) and inactivated by 53.3 +/- 4.9% during a maintained 200-ms depolarization. It was fully available for activation below -80 mV and was completely inactivated by holding potentials more positive than -40 mV. It was completely blocked by 5 mM 4-aminopyridine (4-AP) and by concentrations of tetraethylammonium chloride (TEA) >10 mM. These properties characterize this current as a member of the A-type family of voltage-dependent K(+) currents. The second voltage-gated K(+) current activated at more depolarized potentials (-30 to -20 mV). It activated slower than the A-type current (time-to-peak; 74.1 +/- 3.9 ms at +40 mV) and showed little inactivation (6.2 +/- 2.1%) during a maintained 200-ms depolarization. The current was fully available for activation below -80 mV with a proportion of the current still available for activation at potentials as positive as 0 mV. The current was completely blocked by 1-3 mM TEA. These properties characterize this current as a member of the delayed rectifier family of voltage-dependent K(+) currents. The slow activation rates and relatively depolarized activation thresholds of the two K(+) currents are suggestive that their main role is to contribute to the repolarization phase of the action potential.

4-Aminopyridine↗
PubMed1998

HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers.

We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM), and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1/IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.

Animals↗
PubMed1999

Structure and function of cardiac potassium channels.

Recent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm-1P subunits generally function as inwardly rectifying K(+)-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1-S6). The S5-P-S6 section resembles the 2Tm-1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm-1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit-subunit interactions. The 6Tm-1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm-1P subunits (4Tm-2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm-1P subunits encodes the 'funny' pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm-1P channel enhances the outlook for more refined molecular approaches.

Action Potentials↗
PubMed1997

[Effect of pregnenolone sulfate on delayed rectifier K+ channel in pyramidial neuron of cerebral cortex].

Recent studies have shown that endogenous brain metabolites of steroids may exert important nongenomic modulatory effects on neuronal mechanisms. In this work the effect of pregnenolone sulfate (PS) on delayed rectifier K+ channel (IK) was studied in acutely dissociated rat cerebral cortical pyramidial neurons by means of cell-attached and inside-out patch clamp techniques. The open probability and mean open time of the IK channels were increased by PS in a concentration-dependent manner over the range of 30-100 mumol/L. but without changing the IK amplitude.

Animals↗
PubMed2003

Molecular coupling between voltage sensor and pore opening in the Arabidopsis inward rectifier K+ channel KAT1.

Animal and plant voltage-gated ion channels share a common architecture. They are made up of four subunits and the positive charges on helical S4 segments of the protein in animal K+ channels are the main voltage-sensing elements. The KAT1 channel cloned from Arabidopsis thaliana, despite its structural similarity to animal outward rectifier K+ channels is, however, an inward rectifier. Here we detected KAT1-gating currents due to the existence of an intrinsic voltage sensor in this channel. The measured gating currents evoked in response to hyperpolarizing voltage steps consist of a very fast (tau = 318 +/- 34 micros at -180 mV) and a slower component (4.5 +/- 0.5 ms at -180 mV) representing charge moved when most channels are closed. The observed gating currents precede in time the ionic currents and they are measurable at voltages (less than or equal to -60) at which the channel open probability is negligible ( approximately 10-4). These two observations, together with the fact that there is a delay in the onset of the ionic currents, indicate that gating charge transits between several closed states before the KAT1 channel opens. To gain insight into the molecular mechanisms that give rise to the gating currents and lead to channel opening, we probed external accessibility of S4 domain residues to methanethiosulfonate-ethyltrimethylammonium (MTSET) in both closed and open cysteine-substituted KAT1 channels. The results demonstrate that the putative voltage-sensing charges of S4 move inward when the KAT1 channels open.

Algorithms↗
PubMed2002

Fatty acid augmentation of the cardiac slowly activating delayed rectifier current (IKs) is conferred by hminK.

The mechanism by which dietary fatty acids confer protection against cardiac arrhythmias and sudden cardiac death is not resolved. Here, we study the effects of several known cardio-protective and arrhythmogenic fatty acids on the slowly activating delayed rectifier potassium current (IKs), which is responsible for the repolarization phase of the cardiac action potential. cRNAs encoding either or both of the two subunits, KvLQT1 and hminK, that together produce IKs, were injected into Xenopus oocytes, and the effects of various fatty acids were determined. Docosahexaenoic acid (DHA) significantly augmented IKs as did the short-chained fully saturated lauric acid, and to a lesser extent the cis-unsaturated oleic acid. Eicosapentaenoic acid (EPA) was without significant effect on current magnitude, although it reduced the rate of activation. These results suggest that not all "antiarrhythmic" fatty acids target the same channel. To examine the role of hminK in this response, KvLQT1 was expressed alone. In this case, DHA, lauric acid, and oleic acid did not augment current, suggesting that hminK confers fatty acid sensitivity to IKs.

Animals↗
PubMedDate not supplied

Membrane currents in human intercostal muscle at varied extracellular potassium.

Hyperpolarizing and depolarizing square steps were imposed on the membrane potential of excised human intercostal muscle fibers by means of a 3-microelectrode voltage clamp. The steady-state amplitudes of the membrane currents inducing such steps were investigated as a function of the membrane potential, while the muscle was bathed in solutions varying in potassium content (Ke = 1, 3.5, 7, 20, and 60 mM). At all potassium concentrations, the membrane acted as a rectifier, both in the inward- and outward-going directions. Inward currents were much reduced when Ke was lowered from 3.5 to 1 mM, and were increased when Ke was raised beyond 3.5 mM. The delayed outward current was reduced when Ke was increased from 3.5 mM to 7 mM and higher potassium concentration. The results were qualitatively similar to those reported for rat skeletal muscle.

Cell Membrane↗
PubMed2002

Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents.

The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.

Aniline Compounds↗
PubMed2001

Molecular basis of the delayed rectifier current I(ks)in heart.

J. Kurokawa, H. Abriel and R. S. Kass. Molecular Basis of the Delayed Rectifier Current I(Ks)in Heart. Journal of Molecular and Cellular Cardiology (2001) 33, 873-882. Electrical activity underlies the control of the frequency, strength, and duration of contraction of the heart. During the cardiac cycle, a regular rhythmic pattern must be established in time-dependent changes in ionic conductances in order to ensure events that underlie normal cardiac function. This pattern must be tightly regulated by sympathetic nervous activity to ensure a physiologically relevant relationship between diastolic filling and ejection times with variable heart rate. The duration of the ventricular action potential is controlled in part by a slowly activated potassium channel current, I(Ks). The molecular identity of the subunits that comprise the channels conducting this current is important, not only for understanding the fundamental mechanisms that control electrical activity in healthy individuals, but also for understanding the molecular basis of at least one inherited human disease, LQTS-1. This brief review summarizes key points of information regarding the molecular determinants of the activity of these channels, their relationship to human disease, and what is known, and yet to be discovered, about the molecular determinants of the regulation of this channel by sympathetic nervous activity.

Animals↗
PubMed1993

Integrin-mediated neurite outgrowth in neuroblastoma cells depends on the activation of potassium channels.

Electrical signals elicited by integrin interaction with ECM components and their role in neurite outgrowth were studied in two clones (N1 and N7) isolated from 41A3 murine neuroblastoma cell line. Although the two clones similarly adhered to fibronectin (FN) and vitronectin (VN), this adhesion induced neurite outgrowth in N1 but not in N7 cells. Patch clamp recordings in whole cell configuration showed that, upon adhesion to FN or VN but not to platelet factor 4 (PF4), N1 cells undergo a marked (approximately equal to 20 mV) hyperpolarization of the resting potential (Vrest) that occurred within the first 20 min after cell contact with ECM, and persisted for approximately 1 h before reverting to the time zero values. This hyperpolarization was totally absent in N7 cells. A detailed analysis of the molecular mechanisms involved in N1 and N7 cell adhesion to ECM substrata was performed by using antibodies raised against the FN receptor and synthetic peptides variously competing with the FN or VN binding to integrin receptor (GRGDSP and GRGESP). Antibodies, as well as GRGDSP, abolished adhesion of N1 and N7 clones to FN and VN, revealing a similar implication of integrins in the adhesion of these clones to the ECM proteins. However, these anti-adhesive treatments, while ineffective on Vrest of N7 cells, abolished in N1 cells the FN- or VN-induced hyperpolarization and neurite outgrowth, that appeared therefore strictly associated and integrin-mediated phenomena. The nature of this association was deepened through a comparative analysis of the integrin profiles and the ion channels of N1 and N7 cells. The integrin immunoprecipitation profile resulted very similarly in the two clones, with only minor differences concerning the alpha V containing complexes. Both clones possessed Ca2+ and K+ delayed rectifier (KDR) channels, while only N1 cells were endowed with inward rectifier K+ (KIR) channels. The latter governed the Vrest, and, unlike KDR channels, were blocked by Ba2+ and Cs+. By moving patched cells in contact with FN-coated beads, it was shown that KIR channel activation was responsible for the FN-mediated hyperpolarization of Vrest. Treatment with Pertuxis toxin (PTX) abolished this hyperpolarization and neurite outgrowth, indicating that a G protein is interposed between integrins and KIR channels and that the activation of these channels is required for neuritogenesis. In fact, the block of KIR channels by Cs+ abolished both hyperpolarization and neurite outgrowth, provided that the cation was supplied during the first two hours after N1 cell contact with FN.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMedDate not supplied

The intrinsic dynamics of retinal bipolar cells isolated from tiger salamander.

We studied how intrinsic membrane properties affect the gain and temporal pattern of response in bipolar cells dissociated from retinae of tiger salamanders. Currents specified by a pseudorandom binary sequence, an m-sequence, superimposed on various means, were injected into the cells. From the resultant membrane voltage response for each mean current, impulse responses were estimated. From each impulse response, transfer function, gain, and time constant were calculated. The bipolar cells acted as quasilinear adaptive filters whose gain and response speed are determined by the mean input current. Near resting potential, gain. and time constant were maximum. Dynamics were slow and low-pass, characterized by an approximately exponential impulse response. With depolarization, gains were reduced sharply, responses were much faster, and dynamics became band-pass, as indicated by an undershoot in the impulse response. For any given mean current, the shape of the impulse response did not depend on the amplitude of the m-sequence currents. Thus, bipolar cells behaved in a quasilinear fashion. The adaptive behavior was eliminated by blocking a potassium current, which implicates the role of a voltage-gated potassium conductance. Computer simulations on a model neuron including a delayed-rectifier reconstructed the observed behavior, and provided insight into other, less readily observable, parameters. Thus, bipolar cells, even when isolated, possess mechanisms which regulate, with unsuspected elaborateness, the sensitivities and dynamics of their responsiveness. Implications for adaptation and neuronal processing are discussed.

Ambystoma↗
PubMed1990

Rate-dependent class III antiarrhythmic action, negative chronotropy, and positive inotropy of a novel Ik blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.

The electromechanical effects of UK-68,798 (UK), a novel class III antiarrhythmic drug, were studied in guinea pig and rat papillary muscles (PMs) and atria in vitro using conventional microelectrode technique. UK (10(-8)-10(-6) M) prolonged the action potential duration (APD) by 21-58% and effective refractory period in parallel, without affecting the resting potential or maximum rate of depolarization in guinea pig PM stimulated at 1 Hz. UK increased the contractile force without prolonging the time to peak force or relaxation. In comparison, 5 x 10(-5) M d-sotalol was needed to induce the same electrophysiological effects as 10(-8) M UK. UK prolonged the APD significantly less at 2 Hz than at 1 and 0.5 Hz. Early afterdepolarizations (EADs) developed in 2 of 11 preparations after 10(-6) M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10(-9)-10(-5) M) reduced the spontaneous heart rate and prolonged the sinus node recovery time of guinea pig right atria. No effects on rat PM or atria, even after 10(-5) M, indicate a selective action of UK on the delayed rectifying outward potassium current, Ik. These results indicate a potent and selective, rate-dependent class III antiarrhythmic action of UK-68,798 linked with positive inotropy. Increased APD, bradycardia, and induction of EADs, however, represent a potential arrhythmogenic combination.

Action Potentials↗
PubMed2001

Distinct roles of CaMKII and PKA in regulation of firing patterns and K(+) currents in Drosophila neurons.

The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and the cAMP-dependent protein kinase A (PKA) cascades have been implicated in neural mechanisms underlying learning and memory as supported by mutational analyses of the two enzymes in Drosophila. While there is mounting evidence for their roles in synaptic plasticity, less attention has been directed toward their regulation of neuronal membrane excitability and spike information coding. Here we report genetic and pharmacological analyses of the roles of PKA and CaMKII in the firing patterns and underlying K(+) currents in cultured Drosophila central neurons. Genetic perturbation of the catalytic subunit of PKA (DC0) did not alter the action potential duration but disrupted the frequency coding of spike-train responses to constant current injection in a subpopulation of neurons. In contrast, selective inhibition of CaMKII by the expression of an inhibitory peptide in ala transformants prolonged the spike duration but did not affect the spike frequency coding. Enhanced membrane excitability, indicated by spontaneous bursts of spikes, was observed in CaMKII-inhibited but not in PKA-diminished neurons. In wild-type neurons, the spike train firing patterns were highly reproducible under consistent stimulus conditions. However, disruption of either of these kinase pathways led to variable firing patterns in response to identical current stimuli delivered at a low frequency. Such variability in spike duration and frequency coding may impose problems for precision in signal processing in these protein kinase learning mutants. Pharmacological analyses of mutations that affect specific K(+) channel subunits demonstrated distinct effects of PKA and CaMKII in modulation of the kinetics and amplitude of different K(+) currents. The results suggest that PKA modulates Shaker A-type currents, whereas CaMKII modulates Shal-A type currents plus delayed rectifier Shab currents. Thus differential regulation of K(+) channels may influence the signal handling capability of neurons. This study provides support for the notion that, in addition to synaptic mechanisms, modulations in spike activity patterns may represent an important mechanism for learning and memory that should be explored more fully.

Action Potentials↗