Interactions between calcium channels and SK channels in midbrain dopamine neurons and their impact on pacemaker regularity: Contrasting roles of N- and L-type channels

Although small-conductance Ca²⁺-activated K⁺(SK) channels and various types of voltage-gated Ca²⁺(Ca_v) channels have been described in midbrain dopaminergic neurons, the nature of their interactions is unclear. More particularly, the role of various Ca_vchannel types in either promoting irregularity of firing (by generating an inward current during SK channel blockade) or promoting regularity of firing (by providing the source of Ca²⁺for the activation of SK channels) has not been systematically explored. We addressed this question using intracellular and extracellular recordings from substantia nigra, pars compacta (SNc), dopaminergic neurons in rat midbrain slices. Neurons were pharmacologically isolated from their differences. When examining the ability of various Ca_vchannel blockers to inhibit the SK-mediated afterhyperpolarization (AHP), we found that only the N-type Ca_vchannel blocker ω-conotoxin-GVIA was able to reduce the apamin-sensitive AHP, but only partially (~40%). Specific blockers of L, P/Q, T or R channels had no effect on this AHP. Combining ω-conotoxin-GVIA and other specific blockers did not yield greater block and even the broad Ca_vblocker Cd²⁺induced a submaximal (~75%) effect. Extracellular recordings examining firing regularity yielded congruent results: none of the specific blockers was able to increase firing irregularity to the extent that the specific SK blocker apamin did. The irregularity of firing observed with apamin could only be reversed by blocking L-type Ca²⁺channels. Thus various sources of Ca²⁺appear to be required for SK channel activation in SNc neurons (some of them still unidentified), ensuring robustness of pacemaking regularity.