Universität zu Köln

Despang, Patrick, Salamon, Sarah, Breitenkamp, Alexandra F., Kuzmenkina, Elza, Herzig, Stefan and Matthes, Jan ORCID: 0000-0003-2754-1555 (2020). Autism-associated mutations in the Ca-v beta(2) calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem. Neurobiol. Dis., 136. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-953X

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Abstract

Voltage-gated calcium-channels (VGCCs) are heteromers consisting of several subunits. Mutations in the genes coding for VGCC subunits have been reported to be associated with autism spectrum disorder (ASD). In a previous study, we identified electrophysiologically relevant missense mutations of Ca-v beta(2) subunits of VGCCs. From this, we derived the hypothesis that several Ca-v beta(2)-mutations associated with ASD show common features sensitizing LTCCs and/or enhancing currents. Using a Ca-v beta(2d) backbone, we performed extensive whole-cell and single-channel patch-clamp analyses of Ba2+ currents carried by Ca(v)1.2 pore subunits co-transfected with the previously described Ca-v beta(2) mutations (G167S, S197F) as well as a recently identified point mutation (V2D). Furthermore, the interaction of the mutated Ca-v beta(2) subunits with the RGK protein Gem was analyzed by coimmunoprecipitation assays and electrophysiological studies. Patch-clamp analyses revealed that all mutations increase Ba2+ currents, e.g. by decreasing inactivation or increasing fraction of active sweeps. All Ca-v beta(2) mutations interact with Gem, but differ in the extent and characteristics of modulation by this RGK protein (e.g. decrease of fraction of active sweeps: Ca-v beta(2d_G167S) > Ca-v beta(2d_v2D) > Ca-v beta(2d_S197F). In conclusion, patch-clamp recordings of ASD-associated Ca-v beta(2d) mutations revealed differential modulation of Ba2+ currents carried by Ca(v)1.2 suggesting kind of an electrophysiological fingerprint each. The increase in current finally observed with all Ca-v beta(2d) mutations analyzed might contribute to the complex pathophysiology of ASD and by this indicate a possible underlying molecular mechanism.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Despang, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Salamon, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Breitenkamp, Alexandra F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuzmenkina, Elza UNSPECIFIED UNSPECIFIED UNSPECIFIED Herzig, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Matthes, Jan UNSPECIFIED orcid.org/0000-0003-2754-1555 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-342801
DOI:	10.1016/j.nbd.2019.104721
Journal or Publication Title:	Neurobiol. Dis.
Volume:	136
Date:	2020
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1095-953X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GTP-BINDING PROTEINS; BETA-SUBUNITS; HUMAN HEART; DOMAIN; EXPRESSION; INACTIVATION; INHIBITION; DISORDERS; SURFACE; FAMILY Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34280