Progress in Neuroscience Seminar Series

"Deciphering the mechanisms controlling presynaptic Cav2 subtype levels and organization and their regulation of neurotransmitter release" Samuel M. Young, Jr. PhD Associate Professor Department of Anatomy and Cell Biology, Director of Molecular Auditory Research, Department of Otolaryngology University of Iowa The diversity of information encoding by neuronal circuits is regulated by the magnitude and location of Ca2+ entry though voltage-gated Ca2+ channels (CaV). In the mammalian central nervous system (CNS), CaV2.1 is the critical subtype for CNS function, since it is the most efficient CaV2 subtype triggering action potential (AP) -mediated synaptic vesicle (SV) release. During development, AP-mediated release becomes more CaV2.1 dependent due to a selective reduction of CaV2.2 and CaV2.3 in the presynaptic terminal. Neurons signaling with rapid and temporally precise APs use CaV2.1 exclusive presynapses with fast SV release kinetics. CaV2.1 is the dominant CaV2 isoform associated with human CaV2 channelopathies that manifest in migraine, epilepsy, and ataxia. Dysregulation of SV release is a cause of these and several other neurological disorders. The a1 subunit determines CaV2 subtype and contains multiple motifs implicated in regulating presynaptic CaV2 levels and SV release kinetics. However, little is known about the specific motifs involved and their roles in controlling CaV2.1 levels and SV release kinetics at the presynaptic terminal. Therefore, filling this gap in knowledge is crucial for understanding information encoding by neuronal circuits and the causes of CaV2 channelopathies. To address this fundamental question, we have developed new techniques and applied a combination of functional, molecular, genetic, morphological, and modeling approaches at a synapse in its native environment. In this seminar, we will present our latest findings about the molecular mechanisms controlling presynaptic Cav2 subtype levels and organization and their regulation of neurotransmitter release. Lübbert M, Goral RO, Keine C, Thomas C, Guerrero-Given D, Putzke T, Satterfield R, Kamasawa N, Young SM Jr. (2019) CaV2.1 1 Subunit Expression Regulates Presynaptic CaV2.1 Abundance and Synaptic Strength at a Central Synapse. Neuron. 2019 Jan 16;101(2):260-273.e6. doi: 10.1016/j.neuron.2018.11.028. Epub 2018 Dec 10. Luebbert, M, Goral. R., Satterfield, R. Putzke, T. van den Maagedenburg, A, Kamaswa, N. Young, Jr., SM (2017) A novel region in the CaV2.1 1 subunit C-terminus regulates fast vesicle fusion and vesicle docking at the mammalian presynaptic active zone. Elife. 2017 Aug 8;6. pii: e28412. doi: 10.7554/eLife.28412. Chen, Z., Das B., Nakamura, Y., DiGregorio, D., Young, SM Jr. (2015) Ca2+ Channel to Synaptic Vesicle Distance Accounts for the Readily Releasable Pool Kinetics at a Functionally Mature Auditory Synapse J Neurosci. 35(5):2083-2100