GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

SummaryThe connection from medial habenula (MHb) to interpeduncular nucleus is critical for aversion- and addiction-related behaviors. This pathway is unique in selective expression of R-type voltage-gated Ca2+channels (Cav2.3) in its terminals, and robust potentiation of release via presynaptic GABABreceptors (GBRs). To understand the mechanism underlying this peculiar GBR effect, we examined the presynaptic localization and function of Cav2.3, GBR, and its auxiliary subunits, K+-channel tetramerization domain-containing (KCTD) proteins. We found selective co-expression of KCTD12b and Cav2.3 at the presynaptic active zone. GBR-mediated potentiation remained intact in KCTD12b KO mice but lasted significantly shorter. This impairment was associated with increased release and an insertion of KCTD8 into the active zone. In heterologous cells, we found direct binding of KCTD8 and KCTD12b to Cav2.3, and potentiation of Cav2.3 currents by KCTD8. The unexpected interaction of Cav2.3 with KCTDs therefore provides a means to scale synaptic strength independent of GBR activation.