K+ channels and the regulation of synaptic transmission
Abstract: Neuronal excitability is highly regulated by K+ channels that are activated by a voltage change across the plasma membrane or by a rise in intracellular Na+ or Ca2+ concentration. The main focus of this thesis has been to characterize the Na+-activated K+ (KNa) and the Ca2+-activated K+ (KCa) channels and to determine their role in regulating synaptic transmission in the lamprey spinal cord. Lamprey spinal cord neurons express both KNa and KCa channels with diverse functional roles and sources of Na+ and Ca2+ necessary for their respective activation. There are three routes for Na+ influx to activate KNa in the lamprey spinal cord. The first is through voltage-gated Na+ channels that activate a transient KNa, which is sensitive to TTX and contributes to the early repolarization phase of the action potential. The second route for Na+ entry is through leak channels that activate a sustained KNa current which is blocked by Na+ substitution with Li+, NMDG or choline, but is not affected by TTX. This current appears to underlie the Ca2+-independent component of afterhyperpolarization induced by repetitive firing. The last route of Na+ entry is through AMPA receptors that activate a KNa current which is abolished by Li+ and quinidine. This KNa current has properties similar to the cloned Slack channels, in that it is not modulated by increased intracellular Cl concentration or ATP. The role of the AMPA-induced KNa was examined in excitatory synaptic transmission. KNa channels interact with AMPA receptors in the soma-dendritic region and control the decay time constant of the AMPAmediated current as well as the amplitude of the synaptic potential. Thus, the coupling between KNa channels and AMPA acts as an inherent negative feedback mechanism that depresses the magnitude of excitatory synaptic responses. These AMPA-mediated KNa channels are modulated by activation of metabotropic glutamate receptor 1 (mGluR1). These channels are negatively regulated by activation of mGluR1 which involves PKC. However when intracellular Ca2+ is chelated, mGluR1 positively regulates AMPA-induced KNa channels in a PKCindependent manner. KCa channels are also present in the lamprey spinal cord and are activated by Ca2+ influx via synaptically activated NMDA receptors in the soma-dendritic region. KCa channels are located in close proximity to NMDA receptors and control the decay time constant of the EPSC and the amplitude of the corresponding EPSP. Additionally, KCa channels are also found presynaptically where they are activated by Ca2+ influx through voltage-gated channels. They shape the action potential waveform by determining the duration of the action potential. Thus, KCa channels act both pre- and post-synaptically to limit the extent of excitatory synaptic transmission. In conclusion, different types of both KNa and KCa channels are activated by distinct sources of Na+ and Ca2+ in the lamprey spinal cord. Activation of these channels controls the magnitude of the excitatory response and may regulate the locomotor motor pattern.
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