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

Author:

Bhandari Pradeep1,Vandael David1,Fernández-Fernández Diego2ORCID,Fritzius Thorsten2ORCID,Kleindienst David1,Önal Cihan1ORCID,Montanaro Jacqueline1,Gassmann Martin2,Jonas Peter1ORCID,Kulik Akos34,Bettler Bernhard2,Shigemoto Ryuichi1ORCID,Koppensteiner Peter1ORCID

Affiliation:

1. Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria

2. Department of Biomedicine, University of Basel, Basel, Switzerland

3. Institute of Physiology II, Faculty of Medicine, Freiburg, Germany

4. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany

Abstract

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.

Funder

H2020 European Research Council

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

H2020 Marie Skłodowska-Curie Actions

Deutsche Forschungsgemeinschaft

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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