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

SummaryAction 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.

► Axon initial segment T-type Ca2+ channel activity is downregulated by dopamine
► Dopamine specifically affects AIS T-type channels, not Na+ or K+ channels
► Dopamine lowers axon initial segment excitability, thereby reducing neuronal output
► Endogenous dopamine sources were present in auditory brainstem preparations