Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression
Edward Pym,
Nikhil Sasidharan,
Katherine L Thompson-Peer,
David J Simon,
Anthony Anselmo,
Ruslan Sadreyev,
Qi Hall,
Stephen Nurrish,
Joshua M Kaplan
Affiliations
Edward Pym
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Nikhil Sasidharan
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
David J Simon
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States; Program in Neuroscience, Harvard Medical School, Boston, United States
Anthony Anselmo
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
Ruslan Sadreyev
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
Qi Hall
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Stephen Nurrish
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States; Program in Neuroscience, Harvard Medical School, Boston, United States
Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.
