PMID- 33394222
OWN - NLM
STAT- MEDLINE
DCOM- 20210907
LR  - 20211115
IS  - 1573-6903 (Electronic)
IS  - 0364-3190 (Linking)
VI  - 46
IP  - 3
DP  - 2021 Mar
TI  - Properties of Calmodulin Binding to Na(V)1.2 IQ Motif and Its Autism-Associated 
      Mutation R1902C.
PG  - 523-534
LID - 10.1007/s11064-020-03189-7 [doi]
AB  - Voltage-gated sodium channels (VGSCs) are fundamental to the initiation and 
      propagation of action potentials in excitable cells. Ca(2+)/calmodulin (CaM) 
      binds to VGSC type II (Na(V)1.2) isoleucine and glutamine (IQ) motif. An 
      autism-associated mutation in Na(V)1.2 IQ motif, Arg1902Cys (R1902C), has been 
      reported to affect the combination between CaM and the IQ motif compared to that 
      of the wild type IQ motif. However, the detailed properties for the 
      Ca(2+)-regulated binding of CaM to Na(V)1.2 IQ (1901Lys-1927Lys, IQ(wt)) and 
      mutant IQ motif (IQ(R1902C)) remains unclear. Here, the binding ability of CaM 
      and CaM's constituent proteins including N- and C lobe to the IQ motif of 
      Na(V)1.2 and its mutant was investigated by protein pull-down experiments. We 
      discovered that the combination between CaM and the IQ motif was U-shaped with 
      the highest at [Ca(2+)]  approximately  free and the lowest at 100 nM [Ca(2+)]. In the 
      IQ(R1902C) mutant, Ca(2+)-dependence of CaM binding was nearly lost. 
      Consequently, the binding of CaM to IQ(R1902C) at 100 and 500 nM [Ca(2+)] was 
      increased compared to that of IQ(wt). Both N- and C lobe of CaM could bind with 
      Na(V)1.2 IQ motif and IQ(R1902C) mutant, with the major effect of C lobe. 
      Furthermore, CaMKII had no impact on the binding between CaM and Na(V)1.2 IQ 
      motif. This research offers novel insight to the regulation of Na(V)1.2 IQ(wt) 
      and IQ(R1902C) motif, an autism-associated mutation, by CaM.
FAU - Jia, Wanying
AU  - Jia W
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Liu, Junyan
AU  - Liu J
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Yu, Zhiyi
AU  - Yu Z
AD  - Division of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong 
      University, Jinan, 250012, China.
FAU - Zhang, Xiaohong
AU  - Zhang X
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Xu, Xiaoxue
AU  - Xu X
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Wang, Yuting
AU  - Wang Y
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Gao, Qinghua
AU  - Gao Q
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
AD  - Department of Physiology, Graduate School of Medical and Dental Sciences, 
      Kagoshima University, Kagoshima, 890-8544, Japan.
FAU - Feng, Rui
AU  - Feng R
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Wan, Yujun
AU  - Wan Y
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China.
FAU - Xu, Jianjun
AU  - Xu J
AD  - Department of Physiology, Graduate School of Medical and Dental Sciences, 
      Kagoshima University, Kagoshima, 890-8544, Japan.
FAU - Minobe, Etsuko
AU  - Minobe E
AD  - Department of Physiology, Graduate School of Medical and Dental Sciences, 
      Kagoshima University, Kagoshima, 890-8544, Japan.
FAU - Kameyama, Masaki
AU  - Kameyama M
AD  - Department of Physiology, Graduate School of Medical and Dental Sciences, 
      Kagoshima University, Kagoshima, 890-8544, Japan.
FAU - Wang, Wuyang
AU  - Wang W
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, 221004, China. wuyangwang@126.com.
FAU - Guo, Feng
AU  - Guo F
AUID- ORCID: 0000-0001-9833-9691
AD  - Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical 
      University, Shenyang, 110122, China. blueforest611@hotmail.com.
LA  - eng
GR  - 81971212/National Natural Science Foundation of China/
GR  - 81772559/National Natural Science Foundation of China/
GR  - 81903445/National Natural Science Foundation of China/
GR  - 19K16493/Japan Society for the Promotion of Science Grant-in-Aid for Early-Career 
      Scientists/
PT  - Journal Article
DEP - 20210104
PL  - United States
TA  - Neurochem Res
JT  - Neurochemical research
JID - 7613461
RN  - 0 (Calmodulin)
RN  - 0 (NAV1.2 Voltage-Gated Sodium Channel)
RN  - 0 (SCN2A protein, human)
SB  - IM
MH  - Amino Acid Motifs
MH  - Amino Acid Sequence
MH  - Autistic Disorder/genetics
MH  - Calmodulin/chemistry/*metabolism
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Mutation
MH  - NAV1.2 Voltage-Gated Sodium Channel/chemistry/genetics/*metabolism
MH  - Protein Binding
OTO - NOTNLM
OT  - Autism
OT  - Ca2+/CaM
OT  - IQ motif
OT  - NaV1.2
OT  - R1902C
EDAT- 2021/01/05 06:00
MHDA- 2021/09/08 06:00
CRDT- 2021/01/04 12:16
PHST- 2020/08/03 00:00 [received]
PHST- 2020/11/26 00:00 [accepted]
PHST- 2020/11/15 00:00 [revised]
PHST- 2021/01/05 06:00 [pubmed]
PHST- 2021/09/08 06:00 [medline]
PHST- 2021/01/04 12:16 [entrez]
AID - 10.1007/s11064-020-03189-7 [pii]
AID - 10.1007/s11064-020-03189-7 [doi]
PST - ppublish
SO  - Neurochem Res. 2021 Mar;46(3):523-534. doi: 10.1007/s11064-020-03189-7. Epub 2021 
      Jan 4.