Neuronal L-type calcium channels are regulated by FMR1 and SPOPL
- Susanna Wen.
- Dec. 2013.
- Physical description
- online resource (x, 67 pages) : illustrations (some color)
- Includes bibliographical references (p. 61-67). 66 refs.
- Voltage-gated calcium channels (VGCCs) regulate cellular excitability, differentiation and connectivity. The L-type Ca2+ channel (LTC) CaV1.2 is the most abundant VGCC in the brain, and mis-regulation of LTCs has been linked to bipolar disorder, schizophrenia and autism spectrum disorders. However, how LTC activity is regulated in vivo is incompletely understood. Here we describe a new approach using a high throughput genome-wide screen in Drosophila to identify modulators of CaV1.2 activity. This screen uncovered two novel CaV1.2 regulating proteins, Fragile X Mental Retardation 1 (FMR1) and Speckle-type POZ protein-like (SPOPL). Using biochemistry, calcium-imaging, and electrophysiology in mammalian neurons, we show that FMR1 binds directly to CaV1.2 and regulates its surface expression, while SPOPL alters ubiquitination and electrical properties of the channel. These results reveal new regulatory pathways controlling CaV1.2 activity, and describe a generalizable approach to identifying modulators of LTC function in vivo.
- Calcium Channels, L-Type > physiology
- Systems Biology > methods
- Drosophila melanogaster
- Fragile X Mental Retardation Protein > physiology
- Nuclear Proteins > physiology
- Transcription Factors > metabolism
- Publication date
- Submitted to the Department of Chemical and Systems Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2013.