Universität zu Köln

Papazoglou, Anna, Arshaad, Muhammad Imran, Henseler, Christina, Daubner, Johanna, Broich, Karl, Hescheler, Juergen, Ehninger, Dan, Haenisch, Britta and Weiergraeber, Marco (2022). Ca(v)3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance. Int. J. Mol. Sci., 23 (7). BASEL: MDPI. ISSN 1422-0067

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Abstract

Voltage-gated Ca2+ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca2+ channels were shown to be involved in theta genesis, learning, and memory processes. In particular, HVA Ca(v)2.3 R-type and LVA Ca(v)3 T-type Ca2+ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Ca(v)3 Ca2+ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca2+ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca2+ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer's disease (AD). The age-related downregulation of T-type Ca2+ channels in humans goes together with increased A beta levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca2+ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Papazoglou, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Arshaad, Muhammad Imran UNSPECIFIED UNSPECIFIED UNSPECIFIED Henseler, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Daubner, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Broich, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehninger, Dan UNSPECIFIED UNSPECIFIED UNSPECIFIED Haenisch, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiergraeber, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-678502
DOI:	10.3390/ijms23073457
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	7
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIPPOCAMPAL THETA OSCILLATIONS; GABA-B RECEPTORS; THALAMOCORTICAL RELAY NEURONS; DEPENDENT CALCIUM-CHANNELS; LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; R-TYPE; GABAERGIC NEURONS; MICE LACKING Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67850