Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

Abstract

Neurons of the medial nucleus of the trapezoid body, which transmit auditory information that is used to compute the location of sounds in space, are capable of firing at high frequencies with great temporal precision. We found that elimination of the Kv3.1 gene in mice results in the loss of a high-threshold component of potassium current and failure of the neurons to follow high-frequency stimulation. A partial decrease in Kv3.1 current can be produced in wild-type neurons of the medial nucleus of the trapezoid body by activation of protein kinase C. Paradoxically, activation of protein kinase C increases temporal fidelity and the number of action potentials that are evoked by intermediate frequencies of stimulation. Computer simulations confirm that a partial decrease in Kv3.1 current is sufficient to increase the accuracy of response at intermediate frequencies while impairing responses at high frequencies. We further establish that, of the two isoforms of the Kv3.1 potassium channel that are expressed in these neurons, Kv3.1a and Kv3.1b, the decrease in Kv3.1 current is mediated by selective phosphorylation of the Kv3.1b isoform. Using site-directed mutagenesis, we identify a specific C-terminal phosphorylation site responsible for the observed difference in response of the two isoforms to protein kinase C activation. Our results suggest that modulation of Kv3.1 by phosphorylation allows auditory neurons to tune their responses to different patterns of sensory stimulation.

Coding interaural time differences at low best frequencies in the barn owl

“…This has the effect of minimizing Na þ channel inactivation, allowing cells to reach firing threshold sooner and facilitating high frequency firing. Elimination of the Kv3.1 gene in mice results in the loss of a high-threshold component of potassium current and failure of the neurons to follow high-frequency stimulation [65,120]. Brief action potentials also reduce the amount of neurotransmitter released [99].…”

Deafness associated changes in expression of two-pore domain potassium channels in the rat cochlear nucleus

“…Changes in auditory nerve activity following deafness have been shown to induce changes in excitability and response properties in the cochlear nucleus (Francis and Manis, 2000;Kaltenbach and Afman, 2000;Kanold and Manis, 2005;Wang and Manis, 2005) and inferior colliculus (Bledsoe et al, 1995(Bledsoe et al, , 1997Mossop et al, 2000;Salvi et al, 2000;Syka and Rybalko, 2000;Vale and Sanes, 2002;Vale et al, 2004) (for reviews Moller, 2005;Syka, 2002). While the acoustic environment has been shown to influence auditory brain stem responses through modulation of voltage-gated potassium channels, this is achieved largely through phosphorylation rather than chronic alterations in gene expression (Chambard and Ashmore, 2005;Kaczmarek et al, 2005;Macica et al, 2003;Song et al, 2005). Studies in the avian cochlear nucleus (nucleus magnocellularis) have shown large deafness-related changes in Kv1.1 and Kv3.1 expression following cochlear ablation (Lu et al, 2004;von Hehn et al, 2004).…”

Modulation of Kv3.1b Potassium Channel Phosphorylation in Auditory Neurons by Conventional and Novel Protein Kinase C Isozymes

“…One important physiological specialization enabling MNTB neurons to fire at such high frequencies is the high level of expression of Kv3.1 potassium channels. Genetic knock-out of the Kv3.1 gene, as well as pharmacological and computer modeling studies, confirms that a high threshold component of potassium current in MNTB neurons is carried by Kv3.1 channels and that its elimination impairs the neuronal response to high frequency stimulation (12)(13)(14). Nevertheless, high levels of Kv3.1b current degrade the accuracy of action potential timing at lower frequencies of firing (14 -16).…”

“…The Kv3.1b channel predominates in the mature nervous system and has a longer carboxyl terminus than that of Kv3.1a (2, 17). Activators of PKC significantly reduce the amplitude of Kv3.1b current (14,18,19). Although activation of PKC stimulates phosphate incorporation into several serine residues in Kv3.1b, the specific actions of PKC on Kv3.1b currents have been shown to depend selectively on the phosphorylation of Ser-503 in the carboxyl-terminal region (14).…”