Two Heteromeric Kv1 Potassium Channels Differentially Regulate Action Potential Firing

Abstract

Low-threshold voltage-gated potassium currents (I(LT)) activating close to resting membrane potentials play an important role in shaping action potential (AP) firing patterns. In the medial nucleus of the trapezoid body (MNTB), I(LT) ensures generation of single APs during each EPSP, so that the timing and pattern of AP firing is preserved on transmission across this relay synapse (calyx of Held). This temporal information is critical for computation of sound location using interaural timing and level differences. I(LT) currents are generated by dendrotoxin-I-sensitive, Shaker-related K+ channels; our immunohistochemistry confirms that MNTB neurons express Kv1.1, Kv1.2, and Kv1.6 subunits. We used subunit-specific toxins to separate I(LT) into two components, each contributing approximately one-half of the total low-threshold current: (1) I(LTS), a tityustoxin-Kalpha-sensitive current (TsTX) (known to block Kv1.2 containing channels), and (2) I(LTR), an TsTX-resistant current. Both components were sensitive to the Kv1.1-specific toxin dendrotoxin-K and were insensitive to tetraethylammonium (1 mm). This pharmacological profile excludes homomeric Kv1.1 or Kv1.2 channels and is consistent with I(LTS) channels being Kv1.1/Kv1.2 heteromers, whereas I(LTR) channels are probably Kv1.1/Kv1.6 heteromers. Although they have similar kinetic properties, I(LTS) is critical for generating the phenotypic single AP response of MNTB neurons. Immunohistochemistry confirms that Kv1.1 and Kv1.2 (I(LTS) channels), but not Kv1.6, are concentrated in the first 20 microm of MNTB axons. Our results show that heteromeric channels containing Kv1.2 subunits govern AP firing and suggest that their localization at the initial segment of MNTB axons can explain their dominance of AP firing behavior.

Phosphoinositide Modulation of Heteromeric Kv1 Channels Adjusts Output of Spiral Ganglion Neurons from Hearing Mice

“…Kv1.1-and Kv1.2-specific toxins displayed comparable levels of current inhibition, and their effects were not additive, and so we propose that these subunits comprise a heteromer, rather than two subpopulations of homomeric channels. Kv1.1/Kv1.2 heteromeric channels have been identified elsewhere within the auditory pathway, including the MNTB where they ensure rapid adaptation (Dodson et al, 2002). The properties of auditory neurons in Kv1.1-null and Kv1.2-null mutants have been assessed, but due to the heteromeric nature of the channels, interpretation of the results can be problematic.…”

Unmasking of Spiral Ganglion Neuron Firing Dynamics by Membrane Potential and Neurotrophin-3

“…Further, the K v 1 family of channels are known to form heteromeric and homomeric complexes with differing properties (Ruppersberg et al, 1990;Hopkins et al, 1994), thus adding to the complexity of excitability available to spiral ganglion neurons. Hypothetically, however, a mechanism as simple as depolarization-induced K v 1 inactivation (Dodson et al, 2002) can have a profound effect on the transition to different accommodation classes that would essentially provide instantaneous, yet reversible, regulatory control. Conversely, neurotrophin exposure could activate intracellular signaling systems and engage gene transcription programs that would result in longer-lasting changes in ion channel composition.…”

Posthearing Developmental Refinement of Temporal Processing in Principal Neurons of the Medial Superior Olive

“…The voltage sensitivity, kinetics, and dendrotoxin sensitivity of I K(LVA) in MSO principal cells in many respects resembles that of other brainstem auditory neurons concerned with maintaining the precise timing of excitatory inputs, such as bushy and octopus cells of the VCN, and principal cells of the MNTB (Manis and Marx, 1991;Rathouz and Trussell, 1998;Bal and Oertel, 2001;Dodson et al, 2002;Rothman and Manis, 2003). In situ hybridization and immunocytochemical analyses also reveal that the Kv1.1 subunit is prominently expressed in these brainstem auditory nuclei (Grigg et al, 2000;Dodson et al, 2002;Lu et al, 2004). In the present study, we observed an increase in the amount of I K(LVA) blocked by DTX-K between P14 and P21 (76 to 91% block), possibly reflecting an increase in the proportion of channels containing Kv1.1.…”

“…These developmental changes are mediated primarily by an increase in I K(LVA) . Although MNTB principal neurons also express I K(LVA) (Banks and Smith, 1992;Brew and Forsythe, 1995;Dodson et al, 2002), their intrinsic properties do not change after hearing onset. Thus, the developmental refinement of electrical properties is not a general feature of all time-coding neurons.…”