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Mutagenesis study on the Ca 2+ sensitivity of the SK2 channel
Author(s) -
Siwiecki Sara Ann,
Nam Young Woo,
Whitmore Benjamin,
Orfali Razan,
Zhang Miao
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.991.7
Subject(s) - allosteric regulation , spinocerebellar ataxia , ataxia , neuroscience , channelopathy , ion channel , potassium channel , biophysics , chemistry , medicine , biology , biochemistry , receptor
The cerebellar Purkinje Cells (PCs) are affected in many types of ataxias. The dysfunction of PCs, more specifically the loss of firing precision of PCs, is one of the primary mechanisms underlying the symptoms of ataxia. Disruptions of regular pacemaking activity of PCs have been identified in studies with mouse models of ataxias. Drugs that normalize the regular firing of PCs have been suggested as therapeutics for the symptom of ataxia patients. Small conductance Ca 2+ activated potassium (SK) channels emerged as one of the principle ion channel involved in PCs' pacemaking. Over the past decade, positive allosteric modulators (PAMs) have been developed to target the SK channels. PAMs of SK channels have been shown to alleviate behavioral and neuro‐pathological symptoms in animal models of ataxias. In the SK2 channel, an intrinsically disordered fragment (IDF) at the proximal intracellular C‐terminus connects the transmembrane S6 domain and the CaM binding domain (CaMBD). The flexibility of the IDF makes it a perfect region for the modulation of SK channel activity. The PAMs such as NS309 stabilizes the IDF, and consequently facilitates the coupling between Ca 2+ binding to CaM and opening of the channel. This observation motivated us to introduce mutations in the PAM binding pocket, which also result in changes in the Ca 2+ sensitivity of SK channels. Support or Funding Information American Heart Association SDG Grant, National Ataxia Foundation YI‐SCA Grant to M.Z.