K Ca 2 channel localization and regulation in the axon initial segment.

Small conductance calcium-activated potassium (KCa 2) channels are expressed throughout the CNS and play a critical role in synaptic and neuronal excitability. KCa 2 channels have a somatodendritic distribution with their highest expression in distal dendrites. It is unclear whether KCa 2 channels are specifically present on the axon initial segment (AIS), the site at which action potentials are initiated in neurons. Through a powerful combination of toxin pharmacology, single-molecule atomic force microscopy, and dual-color fluorescence microscopy, we report here that KCa 2 channels-predominantly the KCa 2.3 subtype-are indeed present on the AIS. We also report that cAMP-PKA controls the axonal KCa 2 channel surface expression. Surprisingly, and in contrast to KCa 2 channels that were observed in the soma and dendrites, the inhibition of cAMP-PKA increased the surface expression of KCa 2 channels without promoting nanoclustering. Lastly, we found that axonal KCa 2 channels seem to undergo endocytosis in a dynamin-independent manner, unlike KCa 2 channels in the soma and dendrites. Together, these novel results demonstrate that the distribution and membrane recycling of KCa 2 channels differs among various neuronal subcompartments.-Abiraman, K., Tzingounis, A. V., Lykotrafitis, G. KCa 2 channel localization and regulation in the axon initial segment.