Small conductance calcium-activated potassium (K(Ca)2) channels are expressed throughout the CNS and play a critical role in synaptic and neuronal excitability. K(Ca)2 channels have a somatodendritic distribution with their highest expression in distal dendrites. It is unclear whether K(Ca)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 K(Ca)2 channels-predominantly the K(Ca)2.3 subtype-are indeed present on the AIS. We also report that cAMP-PKA controls the axonal K(Ca)2 channel surface expression. Surprisingly, and in contrast to K(Ca)2 channels that were observed in the soma and dendrites, the inhibition of cAMP-PKA increased the surface expression of K(Ca)2 channels without promoting nanoclustering. Lastly, we found that axonal K(Ca)2 channels seem to undergo endocytosis in a dynamin-independent manner, unlike K(Ca)2 channels in the soma and dendrites. Together, these novel results demonstrate that the distribution and membrane recycling of K(Ca)2 channels differs among various neuronal subcompartments.
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