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

Elife. 2021 Apr 29:10:e68274. doi: 10.7554/eLife.68274.


The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.

Keywords: Cav2.3; KCTD; gabab receptor; interpeduncular nucleus; medial habenula; mouse; neuroscience; r-type calcium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, R-Type / genetics
  • Calcium Channels, R-Type / metabolism*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Habenula / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Presynaptic Terminals / metabolism*
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism*
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism
  • Synapses / genetics
  • Synapses / metabolism


  • Cacna1e protein, mouse
  • Calcium Channels, R-Type
  • Cation Transport Proteins
  • Intracellular Signaling Peptides and Proteins
  • Receptors, GABA
  • Receptors, GABA-B
  • pfetin protein, mouse

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.