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PubMed1978

Potassium channels as multi-ion single-file pores.

A literature review reveals many lines of evidence that both delayed rectifier and inward rectifier potassium channels are multi-ion pores. These include unidirectional flux ratios given by the 2--2.5 power of the electrochemical activity ratio, very steeply voltage-dependent block with monovalent blocking ions, relief of block by permeant ions added to the side opposite from the blocking ion, rectification depending on E--EK, and a minimum in the reversal potential or conductance as external K+ ions are replaced by an equivalent concentration of T1+ ions. We consider a channel with a linear sequence of energy barriers and binding sites. The channel can be occupied by more than one ion at a time, and ions hop in single file into vacant sites with rate constants that depend on barrier heights, membrane potential, and interionic repulsion. Such multi-ion models reproduce qualitatively the special flux properties of potassium channels when the barriers for hopping out of the pore are larger than for hopping between sites within the pore and when there is repulsion between ions. These conditions also produce multiple maxima in the conductance-ion activity relationship. In agreement with Armstrong's hypothesis (1969. J. Gen. Physiol. 54:553--575), inward rectification may be understood in terms of block by an internal blocking cation. Potassium channels must have at least three sites and often contain at least two ions at a time.

Biological Transport↗
PubMed2004

Theoretical possibilities for the development of novel antiarrhythmic drugs.

One possible mechanism of action of the available K-channel blocking agents used to treat arrhythmias is to selectively inhibit the HERG plus MIRP channels, which carry the rapid delayed rectifier outward potassium current (I(Kr)). These antiarrhythmics, like sotalol, dofetilide and ibutilide, have been classified as Class III antiarrhythmics. However, in addition to their beneficial effect, they substantially lengthen ventricular repolarization in a reverse-rate dependent manner. This latter effect, in certain situations, can result in life-threatening polymorphic ventricular tachycardia (torsades de pointes). Selective blockers (chromanol 293B, HMR-1556, L-735,821) of the KvLQT1 plus minK channel, which carriy the slow delayed rectifier potassium current (I(Ks)), were also considered to treat arrhythmias, including atrial fibrillation (AF). However, I(Ks) activates slowly and at a more positive voltage than the plateau of the action potential, therefore it remains uncertain how inhibition of this current would result in a therapeutically meaningful repolarization lengthening. The transient outward potassium current (I(to)), which flows through the Kv 4.3 and Kv 4.2 channels, is relatively large in the atrial cells, which suggests that inhibition of this current may cause substantial prolongation of repolarization predominantly in the atria. Although it was reported that some antiarrhythmic drugs (quinidine, disopyramide, flecainide, propafenone, tedisamil) inhibit I(to), no specific blockers for I(to) are currently available. Similarly, no specific inhibitors for the Kir 2.1, 2.2, 2.3 channels, which carry the inward rectifier potassium current (I(kl)), have been developed making difficult to judge the possible beneficial effects of such drugs in both ventricular arrhythmias and AF. Recently, a specific potassium channel (Kv 1.5 channel) has been described in human atrium, which carries the ultrarapid, delayed rectifier potassium current (I(Kur)). The presence of this current has not been observed in the ventricular muscle, which raises the possibility that by specific inhibition of this channel, atrial repolarization can be lengthened without similar effect in the ventricle. Therefore, AF could be terminated and torsades de pointes arrhythmia avoided. Several compounds were reported to inhibit I(Kur)(flecainide, tedisamil, perhexiline, quinidine, ambasilide, AVE 0118), but none of them can be considered as specific for Kv 1.5 channels. Similarly to Kv 1.5 channels, acetylcholine activated potassium channels carry repolarizing current (I(KAch)) in the atria and not in the ventricle during normal vagal tone and after parasympathetic activation. Specific blockers of I(KAch) can, therefore, also be a possible candidate to treat AF without imposing proarrhythmic risk on the ventricle. At present several compounds (amiodarone, dronedarone, aprindine, pirmenol, SD 3212) were shown to inhibit I(KAch) but none of them proved to be selective. Further research is needed to develop specific K-channel blockers, such as I(Kur)and I(KAch) inhibitors, and to establish their possible therapeutic value.

Action Potentials↗
PubMed1984

Single channel currents in adrenocortical cells.

Single channel currents have been recorded from cell-attached patches of tumoral adrenocortical cells. Our experiments suggest the existence of three sets of potassium channels in the surface membrane of these cells. All channel types can be recorded in a given membrane patch but some patches have only one type of single channel currents. One channel type has a unitary conductance of about 103 pS. The other two channels have smaller conductances and opposite voltage dependence. In one case channels open on depolarization and have a single channel conductance of 31.6 pS. In the other case the probability of being in the open state increases on hyperpolarization and the single channel conductance is of 21 pS. These channels seem to be similar to the delayed and anomalous rectifying potassium channels seen in other preparations. The role of membrane ionic permeability in steroid release induced by ACTH is discussed.

Adrenal Cortex↗
PubMed2000

Mutations affecting the delayed rectifier potassium current in Drosophila.

Mutations and pharmacological agents have been used to resolve and analyze several K(+) currents in Drosophila. Mutations that affect channels carrying the voltage-activated I(A) and the Ca(2+) -activated I(CF) have helped greatly in analyzing the structure, function and regulation of these channels. We now report mutations that selectively affect the delayed rectifier current, I(K). Flies mutagenized with ethylmethanesulfonate were screened for temperature-induced paralysis. Paralytic mutants identified in the screen were examined for K(+) currents in the larval body-wall muscles. The z66 mutant larvae showed a significant reduction in I(K). The mutation did not affect other K(+) currents (I(A), I(CF), or I(CS) ) or the Ca(2+) channel current in the muscles. Another mutation, z4, which showed reduced I(K), failed to complement z66. Genetic analysis localized the gene disrupted by z66 and z4 to the left arm of chromosome 3, in the 63A1-63B6 region on polytene chromosomes. The z66 and the z4 mutations, which lie in the Shab K(+) channel gene, provide an opportunity to undertake analysis of the functioning of these channels and to study the role of these channels in membrane excitability.

Action Potentials↗
PubMed1991

The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy)propanolamines as potential class III antiarrhythmic agents.

The synthesis of 22 (4-methanesulfonamidophenoxy)propanolamines and their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (11a-f) showed residual beta-blocking activity, whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished beta-blocking activity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic Cl and CF3 groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class III antiarrhythmic agents. Methylation of the methanesulfonamido group abolished channel-blocking activity; 4-carboxy and 3-methanesulfonamido analogues retained activity but at a reduced level.

Animals↗
PubMed2001

Alterations of single potassium channel activity in CA1 pyramidal neurons after transient forebrain ischemia.

Selective neuronal injury in the CA1 zone of hippocampus following transient cerebral ischemia has been well documented. Extracellular potassium concentration markedly increases during ischemia/hypoxia. Accumulating evidence has indicated that the outward potassium currents, including delayed rectifier potassium current, not only influence membrane excitability but also mediate apoptosis. It has been shown that the amplitude of delayed rectifier potassium current in CA1 neurons significantly increased after cerebral ischemia. To elucidate the mechanisms underlying the changes of potassium currents following ischemia, single potassium channel activities of rat CA1 neurons were compared before and after transient forebrain ischemia. Using cell-attached configuration, depolarizing voltage steps activated outward single channel events. The channel properties, the kinetics and pharmacology of these events resemble the delayed rectifier potassium current. After ischemia, the unitary amplitude of single channels significantly increased, the open probability, mean open time and open time constant also significantly increased while the conductance remained unchanged. These data indicate that the increase of single channel activity is responsible, at least in part, for the increase of delayed rectifier potassium current in CA1 neurons after cerebral ischemia.

Animals↗
PubMed1997

Inhibition of Toosendanin on the delayed rectifier potassium current in neuroblastoma x glioma NG108-15 cells.

The effect of Toosendanin (TSN), a presynaptic transmission blocker, on the outward delayed rectifier potassium current (IKD) of NG108-15 cells was studied by using the whole-cell voltage-clamp technique. It was observed that externally applying TSN not only reduced IKD amplitude in a dose-dependent and partial reversible manner but also accelerated its inactivation. The effect of internally applying TSN was also examined by including TSN in the electrode, and it was the same as that of externally applying TSN. Further, comparison observations with TEA, 4-AP, verapamil, nifedipine, and (+/-)-Bay K 8644 were also made, and the results were as follows. The time courses of TSN's inhibition effect as well as its recovery after washing were much slower than those of TEA and 4-AP. Externally applying TEA or 4-AP reduced IKD amplitude but did not accelerate its inactivation. Externally applying verapamil, nifedipine, or (+/-)-Bay K 8644, however, similarly to the effect of TSN, not only reduced IKD amplitude but also accelerated its inactivation. Thus, from the obtained results it is suggested that TSN might diffuse into the cell interior and act intracellularly, and the underlying mechanism might be different from that of TEA and 4-AP but similar to that of verapamil, nifedipine, and (+/-)-Bay K 8644 to some extent.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current.

1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic. 2. Long QT syndrome is so-named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents. 3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the 'rapid' cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether-a-go-go-related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram. 4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti-arrhythmics, such as quinidine, non-sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents. 5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K+) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT-prolongation risk of particular agents is important for the clinician.

Action Potentials↗
PubMed1991

Potassium channels and epilepsy: evidence that the epileptogenic toxin, dendrotoxin, binds to potassium channel proteins.

Dendrotoxin-I, a component of the venom of the black mamba snake, Dendroaspis polylepsis, was used to affinity purify a potassium channel from bovine brain. This dendrotoxin-I binding protein was composed of several subunits with molecular weights of 35,000, 38,000, 42,000 and 74,000. Partial sequence resulting from Edman degradation of the N-terminus of the 74 kDa subunit was identical to the predicted amino acid sequence of the N-terminus of a protein encoded by a mouse/rat homologue of the Shaker gene family of potassium channels, MK2/RBK2 (RCK5). Polyclonal antibodies raised against synthetic peptides derived from the predicted amino acid sequence of another member of this family, MK1, recognized this 74 kDa subunit. Due to extensive amino acid sequence identity between MK2 and MK1, it is likely that antibodies recognized epitopes common to both. Thus, from an immunological standpoint, either MK1, MK2, or both channel proteins could have been present in this 74 kDa band on protein blots. Closely related K+ channels in bovine brain could have copurified based on their affinity for dendrotoxin-I (DTX-I). DTX-I was shown to inhibit MK1 currents in a time and voltage independent fashion. Physiological and molecular evidence indicates the existence of many types of DTX sensitive potassium channels in the mammalian brain, however, our protein sequencing of the 74 kDa subunit has detected the presence of only one unique N-terminal sequence, identical to MK2. The possible reason for the appearance of this discrepancy is discussed. This paper represents the first report identifying one dendrotoxin binding protein in bovine brain tissue (BK2) as a delayed rectifier type of potassium channel.

Amino Acid Sequence↗
PubMed2000

Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon.

Protein tyrosine phosphatase epsilon (PTP epsilon) is strongly expressed in the nervous system; however, little is known about its physiological role. We report that mice lacking PTP epsilon exhibit hypomyelination of sciatic nerve axons at an early post-natal age. This occurs together with increased activity of delayed- rectifier, voltage-gated potassium (Kv) channels and with hyperphosphorylation of Kv1.5 and Kv2.1 Kv channel alpha-subunits in sciatic nerve tissue and in primary Schwann cells. PTP epsilon markedly reduces Kv1.5 or Kv2.1 current amplitudes in Xenopus oocytes. Kv2.1 associates with a substrate-trapping mutant of PTP epsilon, and PTP epsilon profoundly reduces Src- or Fyn-stimulated Kv2.1 currents and tyrosine phosphorylation in transfected HEK 293 cells. In all, PTP epsilon antagonizes activation of Kv channels by tyrosine kinases in vivo, and affects Schwann cell function during a critical period of Schwann cell growth and myelination.

Animals↗
PubMed2003

Contribution of ionic currents to magnetoencephalography (MEG) and electroencephalography (EEG) signals generated by guinea-pig CA3 slices.

A mathematical model was used to analyse the contributions of different types of ionic currents in the pyramidal cells of longitudinal CA3 slices to the magnetic fields and field potentials generated by this preparation. Murakami et al. recently showed that a model based on the work of Traub et al. provides a quantitatively accurate account of the basic features of three types of empirical data (magnetic fields outside the slice, extracellular field potentials within the slice and intracellular potentials within the pyramidal neurons) elicited by stimulations of the soma and apical dendrites. This model was used in the present study to compute the net current dipole moment (Q) due to each of the different voltage- and ligand-gated channels in the cells in the presence of fast GABAA inhibition. These values of Q are proportional to the magnetic field and electrical potential far away from the slice. The intrinsic conductances were found to be more important than the synaptic conductances in determining the shape and magnitude of Q. Among the intrinsic conductances, the sodium (gNa) and delayed-rectifier potassium (gK(DR)) channels were found to produce sharp spikes. The high-threshold calcium channel (gCa) and C-type potassium channel (gK(C)) primarily determined the overall current waveforms. The roles of gCa and gK(C) were independent of small perturbations in these channel densities in the apical and basal dendrites. A combination of gNa, gK(DR), gCa, and gK(C) accounted for most of the evoked responses, except for later slow components, which were primarily due to synaptic channels.

Animals↗
PubMed1990

Ion channels in axon and Schwann cell membranes at paranodes of mammalian myelinated fibers studied with patch clamp.

While recent studies have established the presence of voltage-gated ion channels on Schwann cells in culture and on freshly isolated fibers from mature mammals, an important issue not yet explored is whether Schwann cell channels are regionally specialized. In the nodal region, the intimate association between the Schwann cell and its axon suggests that this is a likely site for functional specialization. Here, we examine whether there is a localized expression of channels in the Schwann cell paranodal regions, in a manner similar to that already shown for the nodal axon. Cell-attached and outside-out patch-clamp recordings were made from paranodal regions of rat myelinated sciatic nerve fibers where the myelin on both sides of the node was retracted by enzymatic treatment. Even though no myelin was visible on the surface of the retracted paranode, significant portions of this surface were found to stain positively with a marker (anti-galactocerebroside) for Schwann cell membranes, suggesting that part of the axon still was covered by glial membranes. Using Lucifer yellow in the recording pipettes, we observed that the dye diffused into either axons or Schwann cells when the membrane under the tip was ruptured. Using this as a criterion to identify membranes obtained from retracted paranodes, we found delayed and inwardly rectifying potassium channels on both axon- and Schwann-derived patches. However, sodium channels were detected only in axon patches. This is the first report that voltage-gated glial channels are present in immediate vicinity to axons of the PNS. This finding, coupled with earlier reports that functional channels are absent in soma of mature myelinating Schwann cells, suggests that ion channels in these cells are regionally specialized for functional interaction with axons.

Animals↗
PubMed2001

Expression of the Kv3.1 potassium channel in the avian auditory brainstem.

The Shaw-like potassium channel Kv3.1, a delayed rectifier with a high threshold of activation, is expressed in the time coding nuclei of the bird auditory brainstem. In both barn owls and chickens, Kv3.1 mRNA was expressed in the cochlear nucleus magnocellularis (NM) and the nucleus laminaris (NL). Western blot analysis showed that an antibody raised against the synthetic peptide sequence of rat Kv3.1 (rKv3.1) specifically recognized the same 92 kDa protein bands in both rat and chicken synaptosomal preparations. Immunohistochemical analyses using this anti-rKv3.1 antibody revealed a prominent gradient in Kv3.1 immunoreactivity along the tonotopic axis of the barn owl NM and NL and a less prominent gradient in the chicken. The precise localization of the Kv3.1 immunoproduct was resolved by electron microscopy. In both the owl and the chicken, Kv3.1 was targeted postsynaptically in NM and NL. The major difference in localization of Kv3.1 protein between the two birds was the expression of Kv3.1 in the NM axons and terminals in the region of the barn owl NL. This location of Kv3.1 channels supports its postulated function in reducing the width of action potentials as they invade the presynaptic terminal. The presynaptic localization may be a specialization for enabling neurons in owl NM to transmit high-frequency temporal information with little jitter.

Alternative Splicing↗
PubMed1995

Mechanism of block of a human cardiac potassium channel by terfenadine racemate and enantiomers.

1. The cardiac toxicity of racemic terfenadine (marked QT prolongation and polymorphic ventricular arrhythmias) is probably due to potassium channel blockade. To test whether one of its enantiomers would be a less efficient potassium channel blocker, we compared the mechanism of action of the racemate with that of the individual enantiomers. 2. We synthesized the individual enantiomers of terfenadine and examined under whole cell voltage-clamp conditions the mechanism of action of the racemate, both enantiomers and a major metabolite on a cloned human cardiac potassium channel, hKv1.5. This delayed rectifier is sensitive to quinidine, clofilium and other 'class III' antiarrhythmic drugs at clinically relevant concentrations. 3. Upon depolarization, racemic terfenadine and its enantiomers induced a fast decline of hKv1.5 current towards a reduced steady state current level. During subsequent repolarization the tail currents deactivated more slowly than the control, resulting in a 'crossover' phenomenon. 4. The voltage-dependence of block was biphasic with a steep increase in block over the voltage range of channel opening (-30 to 0 mV), and a more shallow phase positive to 0 mV (where the channel is fully open). The latter was consistent with a binding reaction sensing 21% of the transmembrane electrical field (with reference to the cell interior). 5. The EC50 for hKv1.5 block by racemic terfenadine was 0.88 microM, while the values for R- and S-terfenadine were 1.19 microM and 1.16 microM, respectively. In contrast, the acid metabolite reduced hKv1.5 current by only 5% at a concentration of 50 microM. 6. These findings suggest that terfenadine blocks the hKvl.5 channel after it opens by entering into the internal mouth of the channel. We have previously shown that quinidine blocks hKvl.5 in a similar manner but with an apparent affinity of ~6 micro M. Thus, terfenadine and its enantiomers are approximately equipotent open state blockers of this human K+ channel and about 6 times more potent than quinidine. The similar state-, time-, and voltage-dependence of hKvl.5 block by both enantiomers also indicates that the chiral centre does not significantly constrain the orientation of critical binding determinants of terfenadine with respect to the receptor site.

Animals↗
PubMed2003

Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1.

Mutations in KCNE1, the gene encoding the beta subunit of the slowly activating delayed rectifier potassium current (IKs) channel protein, may lead to the long QT syndrome (LQTS), a condition associated with enhanced arrhythmogenesis. Mice with homozygous deletion of the coding sequence of KCNE1 have inner ear defects strikingly similar to those seen in the corresponding human condition. The present study demonstrated and assessed the mechanism of ventricular arrhythmias in Langendorff-perfused whole heart preparations from homozygous KCNE1-/- mice compared to wild-type mice of the same age. The effects of programmed electrical stimulation with decremental pacing from the basal right ventricular epicardial surface upon electrogram waveforms recorded from the basal left ventricle were assessed and quantified using techniques of paced electrogram fractionation analysis for the first time in an experimental system. All KCNE1-/-(n = 10) but not wild-type (n = 14) mouse hearts empirically demonstrated marked pacing-induced ventricular arrhythmogenicity. This correlated with significant increases in electrogram dispersion, consistent with a wider spread in conduction velocities, in parallel with clinical findings from LQTS patients with potassium channel mutations. In contrast, introduction of 100 nM isoprenaline induced arrhythmogenicity in both KCNE1-/- (n = 7) and wild-type (n = 6) hearts during pacing. Furthermore, pretreatment with 1 muM nifedipine exerted a strong anti-arrhythmic effect in the KCNE1-/- hearts (n = 12) that persisted even in the presence of 100 nM isoprenaline (n = 6). Our findings associate KCNE1-/- with an arrhythmogenic phenotype that shows an increased dispersion of conduction velocities, and whose initiation is prevented by nifedipine, a finding that in turn may have therapeutic applications in conditions such as LQTS.

Adrenergic beta-Agonists↗
PubMed2004

Compound mutations: a common cause of severe long-QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) predisposes affected individuals to sudden death from cardiac arrhythmias. Although most LQTS individuals do not have cardiac events, significant phenotypic variability exists within families. Probands can be very symptomatic. The mechanism of this phenotypic variability is not understood. METHODS AND RESULTS: Genetic analyses of KVLQT1, HERG, KCNE1, KCNE2, and SCN5A detected compound mutations in 20 of 252 LQTS probands (7.9%). Carriers of 2 mutations had longer QTc intervals (527+/-54 versus 489+/-44 ms; P<0.001); all had experienced cardiac events (20 of 20 [100%] versus 128 of 178 [72%]; P<0.01) and were 3.5-fold more likely to have cardiac arrest (9 of 16 [56%] versus 45 of 167 [27%]; P<0.01; OR, 3.5; 95% CI, 1.2 to 9.9) compared with probands with 1 or no identified mutation. Two-microelectrode voltage clamp of Xenopus oocytes was used to characterize the properties of variant slow delayed rectifier potassium (I(Ks)) channels identified in 7 of the probands. When wild-type and variant subunits were coexpressed in appropriate ratios to mimic the genotype of the proband, the reduction in I(Ks) density was equivalent to the additive effects of the single mutations. CONCLUSIONS: LQTS-associated compound mutations cause a severe phenotype and are more common than expected. Individuals with compound mutations need to be identified, and their management should be tailored to their increased risk for arrhythmias.

Animals↗
PubMed2003

The structure and ion channel activity of 6-benzylamino-3-hydroxyhexa-cyclo[6.5.0.0(3,7).0(4,12).0(5,10).0(9,13]tridecane.

A novel compound, 6-benzylamino-3-hydroxyhexacyclo [6.5.0.0(3, 7).0(4, 12).0(5, 10).0(9, 13)]-tridecane, was synthesized as part of an ongoing study to explore the ion channel activity of polycyclic cage amines. The known polycyclic calcium channel antagonist, 8-benzylamino-8, 11-oxapentacyclo [5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane (NGP 1-01) served as the lead compound and as a positive control for channel activity. The title compound inhibited calcium currents at test concentrations of 10 microM at depolarized membrane potentials (in the potential range where the L-type calcium channel inactivates). At the test concentrations modulating effects were also observed for sodium and the delayed rectifier potassium currents. Due to its activity at both Ca(2+) and Na(+) channels, this compound may offer utility as a cardiovascular and/or neuroprotecting agent.

Animals↗
PubMed1993

Convergence of auditory nerve fibers onto bushy cells in the ventral cochlear nucleus: implications of a computational model.

1. Convergence of auditory nerve (AN) fibers onto bushy cells of the ventral cochlear nucleus (VCN) was investigated with a model that describes the electrical membrane properties of these cells. The model consists of a single compartment, representing the soma, and includes three voltage-sensitive ion channels (fast sodium, delayed-rectifier-like potassium, and low-threshold potassium). These three channels have characteristics derived from voltage clamp data of VCN bushy cells. The model also contains a leakage channel, membrane capacitance, and synaptic inputs. The model accurately reproduces the membrane rectification seen in current clamp studies of bushy cells, as well as their unique current clamp responses. 2. In this study, the number and synaptic strength of excitatory AN inputs to the model were varied to investigate the relationship between input convergence parameters and response characteristics. From 1 to 20 excitatory synaptic inputs were applied through channels in parallel with the voltage-gated channels. Each synapse was driven by an independent AN spike train; spike arrivals produced brief (approximately 0.5 ms) conductance increases. The number (NS) and conductance (AE) of these inputs were systematically varied. The input spike trains were generated as a renewal point process that accurately models characteristics of AN fibers (refractoriness, adaptation, onset latency, irregularity of discharge, and phase locking). Adaptation characteristics of both high and low spontaneous rate (SR) AN fibers were simulated. 3. As NS and AE vary over the ranges 1-20 and 3-80 nS, respectively, the full range of response types seen in VCN bushy cells are produced by the model, with AN inputs typical of high-SR AN fibers. These include primarylike (PL), primarylike-with-notch (Pri-N), and onset-L (On-L). In addition, Onset responses, whose association with bushy cells in uncertain, and "dip" responses, which are not seen in the VCN, are produced. Dip responses occur with large NS and/or AE, and are due to depolarization block. When the AN inputs have the adaptation characteristics of low-SR AN fibers, PL--but not Pri-N or On-L responses--are produced. This suggests that neurons showing Pri-N and On-L responses must receive high-SR AN inputs. 4. The regularity of discharge of the model is compared with that of VCN bushy cells, using a measure derived from the mean and standard deviation of interspike intervals. Regularity is an important constraint on the model because the regularity of VCN bushy cells is the same as that of their AN inputs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗