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Title: Trafficking of N-type voltage-gated calcium ion channels and their regulation by alternative splicing
Author: Macabuag, N.
ISNI:       0000 0004 7229 4968
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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N-type voltage-gated calcium (CaV2.2) channels are expressed predominantly in the central and peripheral nervous systems and play a crucial role in neurotransmitter release. Expression of these channels at the plasma membrane and in the membrane of presynaptic terminals is key for their function, however, how they are trafficked from the subcellular organelles is still poorly understood. In this study, trafficking of mutually-exclusive alternative splice variants of CaV2.2, containing either exon 37a or 37b at the proximal C-terminus and its mechanisms were examined. CaV2.2 with exon 37a (selectively expressed in nociceptors) reveals a significantly greater intracellular trafficking to the axons and plasma membrane of DRG neurons than CaV2.2 with exon 37b. Further examination of the amino acid sequence in exon 37 uncovers that the canonical binding motifs for adaptor protein 1 (AP-1), YxxΦ and [DE]xxxL[LI], present only in exon 37a are accountable for mediating the enhanced channel trafficking from the trans-Golgi network to the plasma membrane. Finally, the dopamine-2 receptor (D2R) and its agonist-induced activation, reveal differential effects on trafficking of these CaV2.2 isoforms. D2R slowed the endocytosis of CaV2.2 containing exon 37b but not exon 37a, and activation by the D2R-selective agonist quinpirole reversed the effect of the D2R. Disrupting the interaction between adaptor proteins and YxxΦ or [DE]xxxL[LI] in CaV2.2 perturbed these effects, suggesting that the interaction of adaptor proteins with CaV2.2 channels may also be key underlying mechanisms for differential trafficking of CaV2.2 splice variants, mediated by D2R. This study thus reveals key mechanisms involved in the trafficking of N-type calcium channels.
Supervisor: Dolphin, A. C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available