Authors:	Krick, Niklas
Title:	Functional separation of two distinct voltage gated calcium channels at the presynaptic terminal of Drosophila larval crawling motoneurons
Online publication date:	10-Nov-2020
Year of first publication:	2020
Language:	english
Abstract:	At the presynaptic terminal of chemical synapses, release probability of synaptic vesicles must be tightly controlled, while at the same time vesicle recycling and changes in release probability need to occur side by side and must be dynamically adapted to a changing external input and internal state. These three mechanisms are heavily calcium dependent thus needing different calcium nano- and/or microdomains with specific spatio-temporal identities. Calcium nano- and/or microdomains are produced by clusters of voltage gated calcium channels (VGCC), and the characteristics depend on the abundance and individual gating properties of the respective calcium channels and on the calcium buffering properties of soluble buffers, calcium binding proteins and extrusion pumps. Hence, the major questions of this thesis are, what is the underlying mechanism that enables separate regulation of these crucial, calcium dependent presynaptic mechanisms and what are its molecular components. Combining Drosophila genetics, electrophysiology and imaging techniques, I uncover a new mechanism that allows simultaneous calcium signaling for exo and endocytosis in the limited space of presynaptic terminals. In Drosophila three genes for VGCCs exist, Dmca1D, a homolog of vertebrate Cav1 channels, Dmca1A, the Cav2 homolog and DmαG as a homolog for vertebrate Cav3 channels. It has long been known that action potential triggered SV exocytosis is mediated by calcium influx through the Dmca1A calcium channel that localizes in the active zone, in close proximity to the readily releasable vesicle pool. In this thesis, I now discovered that action potential mediated calcium signaling for short term plasticity, as well as activity dependent endocytosis regulation, are mediated via the Dmca1D calcium channel, localized outside the active zone. Even though exo- and endocytosis need to occur on different timescales and rely on different calcium concentrations, I demonstrate that despite the physical distance between both calcium sources, the active zone calcium nanodomain for exocytosis is actively protected from peri-active zone calcium signaling by the plasma membrane bound calcium ATPase PMCA. This newly identified mechanism of separate yet parallel calcium signaling significantly increases the understanding of presynaptic calcium handling during activity and gives rise to conceptually new functions of peri-active zone molecules and their effects on stable presynaptic function and plasticity.
DDC:	500 Naturwissenschaften 500 Natural sciences and mathematics
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-5321
URN:	urn:nbn:de:hebis:77-openscience-e2badc39-f1e5-4385-bd8a-5ef6706cd3ff5
Version:	Original work
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	https://rightsstatements.org/vocab/InC/1.0/
Extent:	69 Seiten
Appears in collections:	JGU-Publikationen