title: RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca²⁺-dependent inactivation.
abstract: Adenosine-to-inosine RNA editing is crucial for generating molecular diversity, and serves to regulate protein function through recoding of genomic information. Here, we discover editing within Ca(v)1.3 Ca²⁺ channels, renown for low-voltage Ca²⁺-influx and neuronal pacemaking. Significantly, editing occurs within the channel's IQ domain, a calmodulin-binding site mediating inhibitory Ca²⁺-feedback (CDI) on channels. The editing turns out to require RNA adenosine deaminase ADAR2, whose variable activity could underlie a spatially diverse pattern of Ca(v)1.3 editing seen across the brain. Edited Ca(v)1.3 protein is detected both in brain tissue and within the surface membrane of primary neurons. Functionally, edited Ca(v)1.3 channels exhibit strong reduction of CDI; in particular, neurons within the suprachiasmatic nucleus show diminished CDI, with higher frequencies of repetitive action-potential and calcium-spike activity, in wild-type versus ADAR2 knockout mice. Our study reveals a mechanism for fine-tuning Ca(v)1.3 channel properties in CNS, which likely impacts a broad spectrum of neurobiological functions.
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597 Singapore.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Bao Zhen
authors.initials: BZ
authors.lastname: Tan
authors.forename: Yiru
authors.initials: Y
authors.lastname: Shen
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.forename: Fengli
authors.initials: F
authors.lastname: Jiang
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Sung
authors.forename: Choon Keow
authors.initials: CK
authors.lastname: Ng
authors.forename: Manfred
authors.initials: M
authors.lastname: Raida
authors.forename: Georg
authors.initials: G
authors.lastname: Köhr
authors.forename: Miyoko
authors.initials: M
authors.lastname: Higuchi
authors.forename: Hadi
authors.initials: H
authors.lastname: Fatemi-Shariatpanahi
authors.forename: Bradley
authors.initials: B
authors.lastname: Harden
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D017393:RNA Editing; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D002118:Calcium