Sodium Channel β2 Subunits Prevent Action Potential Propagation Failures at Axonal Branch Points.

Neurotransmitter release depends on voltage-gated Na+ channels (Navs) to propagate an action potential (AP) successfully from the axon hillock to a synaptic terminal. Unmyelinated sections of axon are very diverse structures encompassing branch points and numerous presynaptic terminals with undefined molecular partners of Na+ channels. Using optical recordings of Ca2+ and membrane voltage, we demonstrate here that N+ channel β2 subunits (Navβ2s) are required to prevent AP propagation failures across the axonal arborization of cultured rat hippocampal neurons (mixed male and female). When Nav/32 expression was reduced, we identified two specific phenotypes: (1) membrane excitability and AP-evoked Ca2+ entry were impaired at synapses and (2) AP propagation was severely compromised with >40% of axonal branches no longer responding to AP-stimulation. We went on to show that a great deal of electrical signaling heterogeneity exists in AP waveforms across the axonal arborization independent of axon morphology. Therefore, Navβ2 is a critical regulator of axonal excitability and synaptic function in unmyelinated axons. [ABSTRACT FROM AUTHOR]