Seizures and Reduced Life Span in Mice Lacking the Potassium Channel Subunit Kv1.2, but Hypoexcitability and Enlarged Kv1 Currents in Auditory Neurons

2007 ◽  
Vol 98 (3) ◽  
pp. 1501-1525 ◽  
Author(s):  
Helen M. Brew ◽  
Joshua X. Gittelman ◽  
Robert S. Silverstein ◽  
Timothy D. Hanks ◽  
Vas P. Demas ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Low Voltage ◽  
Seizure Susceptibility ◽  
Auditory Neurons ◽  
Medial Nucleus ◽  
Voltage Dependent ◽  
Similar Phenotype ◽  
Brain Stem Slices ◽  
Trapezoid Body ◽  
Fine Tune

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage–activated potassium current IKv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced IKv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (−/−). The −/− mice exhibited increased seizure susceptibility compared with their +/+ and +/− littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from −/− and +/− mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped −/− MNTB neurons had enlarged IKv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/− Kv1 channels, and no −/− Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger IKv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

Activation and Deactivation of Voltage-Dependent K+ Channels During Synaptically Driven Action Potentials in the MNTB

2006 ◽  
Vol 96 (3) ◽  
pp. 1547-1555 ◽  
Author(s):  
Achim Klug ◽  
Laurence O. Trussell
Keyword(s):  
Action Potentials ◽  
Time Course ◽  
Low Voltage ◽  
Multiple Roles ◽  
Synaptic Activity ◽  
Leak Current ◽  
Medial Nucleus ◽  
Voltage Dependent ◽  
Spike Waveforms ◽  
Trapezoid Body

K+ channels shape individual action potentials and determine their pattern of firing. In auditory relays, both high- and low-voltage–activated K+ channels (HVA and LVA) are critical for preservation of auditory timing cues. We examined how these channels participate in firing in the medial nucleus of the trapezoid body. Principal cells at physiological temperature were voltage clamped using spike waveforms previously recorded in response to calyceal firing. Current components were isolated by digital subtraction of traces recorded in the channel antagonists dendrotoxin-I or tetraethylammonium. During orthodromic spikes delivered at 300 and 600 Hz, both currents activated with a slight delay, peaking just after the crest of the spike. The decay of HVA was sufficiently fast to match the time course of the spike. By contrast, with 300-Hz stimuli, LVA continued to decay after the spikes reached a stable interspike potential. Although LVA currents partially inactivate during prolonged voltage steps, their peak amplitudes remained stable or increased during trains of spikelike stimuli. At 600 Hz, LVA did not fully deactivate between the spikes and therefore generated a leak current. To determine the effect of blocking LVA channels on spiking, prerecorded postsynaptic conductances were injected, with and without dendrotoxin-I. After block of LVA channels, strong synaptic conductances produced broader spikes, greater spike jitter, and prolonged depolarized states. HVA blockade with tetraethylammonium also broadened spikes but led to less error in timing. These results reveal multiple roles for LVA channels in spike repolarization and timing during synaptic activity.

Extraction of Auditory Information by Modulation of Neuronal Ion Channels

2018 ◽  
pp. 272-300
Author(s):  
Leonard K. Kaczmarek
Keyword(s):  
Ion Channels ◽  
Neuronal Firing ◽  
Auditory Information ◽  
Auditory Neurons ◽  
Complex Sound ◽  
Medial Nucleus ◽  
Rapid Changes ◽  
Genes Encoding ◽  
Kinetics Of ◽  
Trapezoid Body

All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.

Differential distribution of potassium channels in acutely demyelinated, primary-auditory neurons in vitro

1996 ◽  
Vol 76 (1) ◽  
pp. 438-447 ◽  
Author(s):  
R. L. Davis
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Myelin Sheath ◽  
Lucifer Yellow ◽  
The Other ◽  
K Channel ◽  
Channel Activity ◽  
Auditory Neurons ◽  
Axonal Membrane ◽  
Voltage Dependent

1. Single-channel recordings of potassium channel activity were made from two populations of primary-auditory neurons maintained in tissue culture. The saccular nerve, which is the auditory component of the eighth cranial nerve in goldfish, was separated into two branches according to its peripheral innervation pattern. Neurons which innervated the rostral saccular macula corresponded to a class of cells that showed spike frequency adaptation; whereas, neurons which innervated the caudal macula were consistent with another type of cell that demonstrated bursting spontaneous firing patterns in vivo. Both somatic and internodal axonal membranes from each of these neuronal classes were studied after acute removal of the myelin sheath by microdissection. 2. Dye injections were used to discriminate neuronal from myelin membrane. After successful removal of the myelin, patch electrodes containing Lucifer yellow were used to fill a neuron and reveal its morphology within the myelin sheath. Patches on myelin led to filling of Schwann cells that surrounded the neuron. 3. Four kinds of potassium channels were observed and characterized according to unitary conductance, inactivation, and sensitivity to internal calcium. Three voltage-dependent K+ channel types were found on the somatic and axonal membrane of the two neuronal populations. Two channel types showed voltage-dependent inactivation and had average conductances of 32 and 19 pS, each with distinctive subconductance states. The third type of channel activity had an estimated conductance of 12 pS and was noninactivating. 4. The fourth type of channel was the Ca2(+)-activated K+ channel (k(Ca)), which was classified by the dependence of its activity on the calcium concentration at its cytoplasmic surface. Unlike the other three potassium channel types, this kind of channel was found exclusively on neurons that innervated the caudal sensory epithelium. As with the other kinds of potassium channels, it was found on both somatic and axonal internodal membranes.

Hyperpolarization-activated cation current (Ih) in neurons of the medial nucleus of the trapezoid body: voltage-clamp analysis and enhancement by norepinephrine and cAMP suggest a modulatory mechanism in the auditory brain stem

1993 ◽  
Vol 70 (4) ◽  
pp. 1420-1432 ◽  
Author(s):  
M. I. Banks ◽  
R. A. Pearce ◽  
P. H. Smith
Keyword(s):  
Voltage Clamp ◽  
Membrane Conductance ◽  
Activation Time ◽  
Current Clamp ◽  
Activation Curve ◽  
Medial Nucleus ◽  
Cation Current ◽  
Voltage Dependent ◽  
Low Threshold ◽  
Trapezoid Body

1. Principal cells in the medial nucleus of the trapezoid body (MNTB) are part of a circuit in the superior olivary complex (SOC) that processes binaural information important for sound localization. MNTB cells have two voltage-dependent currents active near rest that contribute to these cells' highly nonlinear membrane properties and shape their responses to synaptic input. One of these currents, a low-threshold, 4-aminopyridine (4-AP)-sensitive K+ current, has been studied previously under current clamp. Using the single-electrode voltage-clamp technique, we have investigated the other of these currents, a hyperpolarization-activated, mixed cation current (Ih), in brain slices of the rat SOC. 2. Ih is responsible for a prominent "sag" in the voltage response to a steady hyperpolarizing current recorded under current clamp in MNTB cells. In voltage-clamp recordings, hyperpolarizing voltage steps from the resting potential elicited a large inward current that activated and deactivated with biexponential kinetics. Activation time constants were voltage dependent, with tau 1 and tau 2 = 246 and 1620 ms at -75 mV and 107 and 560 ms at -100 mV. 3. Ih was blocked by 1-5 mM cesium and had a reversal potential of -43 mV. Steady-state activation curves derived from tail currents yielded a half-activation voltage of -75.7 mV and slope factor of 5.7 mV, corresponding to < 10% activation of Ih at rest. 4. Application of norepinephrine (15-20 microM) or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) (1 mM) caused a depolarizing shift in the steady-state activation curve and decreased the activation time constants. The shift in the activation curve resulted in a large increase in the activation of Ih at rest, an inward shift in the holding current, and an increase in the resting membrane conductance. In current-clamp recordings, this increase in the resting activation level of Ih resulted in membrane depolarization of 2-3 mV in the absence of 4-AP, and 5-10 mV in the presence of 4-AP, an increase in the input conductance, and a reduction in the voltage sag in response to hyperpolarizing currents. 5. The resulting change in the resting point of MNTB cells exposed to norepinephrine or 8-Br-cAMP is likely to alter the responses of these cells to synaptic input, both via the direct effect on the resting membrane conductance and by changing the activation of the low-threshold, 4-AP-sensitive potassium current.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Cooperative interactions among subunits of a voltage-dependent potassium channel. Evidence from expression of concatenated cDNAs.

1992 ◽  
Vol 267 (33) ◽  
pp. 23742-23745
Author(s):  
R.S. Hurst ◽  
M.P. Kavanaugh ◽  
J Yakel ◽  
J.P. Adelman ◽  
R.A. North
Keyword(s):  
Potassium Channel ◽  
Cooperative Interactions ◽  
Voltage Dependent

scholarly journals Low-voltage activated (LVA) inward current in murine antral smooth muscle cells is an artifact

2021 ◽  
Author(s):  
Ji Yeon Lee ◽  
Haifeng Zheng ◽  
Kenton M. Sanders ◽  
Sang Don Koh
Keyword(s):  
Low Voltage ◽  
External Solution ◽  
Physiological Salt Solution ◽  
Channel Blockers ◽  
Free Solution ◽  
Inward Current ◽  
High K ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Rich Solution

We characterized the two types of voltage-dependent inward currents in murine antral SMC. The HVA and LVA inward currents were identified when cells were bathed in Ca2+-containing physiological salt solution. We examined whether the LVA inward current was due to: 1) T-type Ca2+ channels, 2) Ca2+-activated Cl- channels, 3) non-selective cation channels (NSCC) or 4) voltage-dependent K+ channels with internal Cs+-rich solution. Replacement of external Ca2+ (2 mM) with equimolar Ba2+ increased the amplitude of the HVA current but blocked the LVA current. Nicardipine blocked the HVA current, and in the presence of nicardipine, T-type Ca2+ blockers failed to block LVA. The Cl- channel antagonist had little effect on LVA. Cation-free external solution completely abolished both HVA and LVA. Addition of Ca2+ in cation-free solution restored only HVA currents. Addition of K+ (5 mM) to cation-free solution induced LVA current that reversed at -20 mV. These data suggest that LVA is not due to T-type Ca2+ channels, Ca2+-activated Cl- channels or NSCC. Antral SMC express A-type K+ currents (KA) and delayed rectifying K+ currents (KV) with dialysis of high K+ (140 mM) solution. When cells were exposed to high K+ external solution with dialysis of Cs+-rich solution in the presence of nicardipine, LVA was evoked and reversed at positive potentials. These HK-induced inward currents were blocked by K+ channel blockers, 4-aminopyridine and TEA. In conclusion, LVA inward currents can be generated by K+ influx via KA and KV channels in murine antral SMC when cells were dialyzed with Cs+-rich solution.

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