Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains
Luna Gao,
Jian Zhao,
Evan Ardiel,
Qi Hall,
Stephen Nurrish,
Joshua M Kaplan
Affiliations
Luna Gao
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Jian Zhao
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Evan Ardiel
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
Qi Hall
Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
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
Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here, we show that the Caenorhabditis elegans SHN-1/Shank promotes CaV1 coupling to calcium activated potassium channels. Mutations inactivating SHN-1, and those preventing SHN-1 binding to EGL-19/CaV1 all increase action potential durations in body muscles. Action potential repolarization is mediated by two classes of potassium channels: SHK-1/KCNA and SLO-1 and SLO-2 BK channels. BK channels are calcium-dependent, and their activation requires tight coupling to EGL-19/CaV1 channels. SHN-1’s effects on AP duration are mediated by changes in BK channels. In shn-1 mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased shn-1 gene copy number produce similar changes in AP width and SLO-2 current. Collectively, these results suggest that an important function of Shank is to promote microdomain coupling of BK with CaV1.
