The role of voltage-gated potassium channels in regulating excitability at a central synapse
thesisposted on 15.12.2014, 10:34 by Paul D. Dodson
The medial nucleus of the trapezoid body (MNTB) rapidly and precisely relays auditory information used to determine where a sound is originating from. Voltage-gated K+ channels play an important role in this process by preserving action potential (AP) timing. We investigated the subunit composition of K+ channels and their role of regulating AP firing in a giant presynaptic terminal (the calyx of Held) and its postsynaptic neurones (MNTB neurones) by combining patch-clamp recordings and immunohistochemistry in brainstem slices from 8-14 day Lister hooded rats and C57/B16 mice. Kvl currents in MNTB neurones were completely blocked by dendrotoxin-K (DTX-K, which blocks Kvl.l containing channels) but only half blocked by tityustoxin-Ka (TsTX-Ka, which blocks channels containing Kvl.2 or Kvl.3). Combined with immunohistochemical evidence that only Kvl.l, Kvl.2 and Kvl.6 are present, these data indicate that Kvl. 1/1.2 and Kvl. 1/1.6 heteromers mediate the Kvl current. Block of Kvl. 1/1.2 heteromers disrupted unitary firing, signifying that it is these channels which preserve AP firing fidelity. In the presynaptic terminal, Kvl currents were completely blocked by TsTX-Ka but only partially by DTX-K, indicating that Kvl.2 homomers mediate two-thirds of this current, with the remaining third mediated by Kvl. 1/1.2 heteromers. Block of Kvl.2 homomers caused aberrant AP firing, suggesting that these channels preserve precise presynaptic AP firing by preventing nerve terminal hyperexcitability. Presynaptic Kv3 currents were mediated by channels containing Kv3.1, Kv3.3 and Kv3.4 sub units. These channels were resistant to phosphorylation and activated at more negative potentials than their postsynaptic counterparts. These data suggest that specialisations in subunit composition enable Kv3 channels to rapidly repolarise the presynaptic AP, facilitating high frequency firing. This work not only demonstrates the role of different K+ channels in preserving reliable high frequency firing at this central synapse, but also highlights how subunit composition can influence the role of K+ channels in the CNS.