Dopaminergic Modulation of Axon Initial Segment Calcium Channels Regulates Action Potential Initiation

Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na⁺ and K⁺ channels. Recently, we found that T- and R-type Ca²⁺ channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca²⁺ channel activity in brainstem interneurons. T-type Ca²⁺ channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na⁺ or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by specifically regulating Ca²⁺ channels directly involved in action potential initiation.