PMID- 35726573
OWN - NLM
STAT- MEDLINE
DCOM- 20220701
LR  - 20240514
IS  - 1744-8069 (Electronic)
IS  - 1744-8069 (Linking)
VI  - 18
DP  - 2022 Apr
TI  - Nociceptive signaling through transient receptor potential vanilloid 1 is 
      regulated by Cyclin Dependent Kinase 5-mediated phosphorylation of T407 in vivo.
PG  - 17448069221111473
LID - 10.1177/17448069221111473 [doi]
LID - 17448069221111473
AB  - Cyclin dependent kinase 5 (Cdk5) is a key neuronal kinase whose activity can 
      modulate thermo-, mechano-, and chemo-nociception. Cdk5 can modulate nociceptor 
      firing by phosphorylating pain transducing ion channels like the transient 
      receptor potential vanilloid 1 (TRPV1), a thermoreceptor that is activated by 
      noxious heat, acidity, and capsaicin. TRPV1 is phosphorylated by Cdk5 at 
      threonine-407 (T407), which then inhibits Ca(2+) dependent desensitization. To 
      explore the in vivo implications of Cdk5-mediated TRPV1 phosphorylation on pain 
      perception, we engineered a phospho-null mouse where we replaced T407 with 
      alanine (T407A). The T407A point mutation did not affect the expression of TRPV1 
      in nociceptors of the dorsal root ganglia and trigeminal ganglia (TG). However, 
      behavioral tests showed that the TRPV1(T407A) knock-in mice have reduced aversion 
      to oral capsaicin along with a trend towards decreased facial displays of pain 
      after a subcutaneous injection of capsaicin into the vibrissal pad. In addition, 
      the TRPV1(T407A) mice display basal thermal hypoalgesia with increased paw 
      withdrawal latency while tested on a hot plate. These results indicate that 
      phosphorylation of TRPV1 by Cdk5 can have important consequences on pain 
      perception, as loss of the Cdk5 phosphorylation site reduced capsaicin- and 
      heat-evoked pain behaviors in mice.
FAU - Cho, Andrew
AU  - Cho A
AD  - Gene Transfer Core, National Institute of Dental and Craniofacial Research, 
      National Institutes of Health, Bethesda, MD, USA.
FAU - Hall, Bradford E
AU  - Hall BE
AD  - Functional Genomics Section, National Institute of Dental and Craniofacial 
      Research, 2511National Institutes of Health, Bethesda, MD, USA.
FAU - Limaye, Advait S
AU  - Limaye AS
AD  - Gene Transfer Core, National Institute of Dental and Craniofacial Research, 
      National Institutes of Health, Bethesda, MD, USA.
FAU - Wang, Sheng
AU  - Wang S
AD  - Department of Neural and Pain Sciences, School of Dentistry, Program in 
      Neuroscience, Center to Advance Chronic Pain Research, 12264The University of 
      Maryland, Baltimore, MD, USA.
FAU - Chung, Man-Kyo
AU  - Chung MK
AUID- ORCID: 0000-0001-7637-1148
AD  - Department of Neural and Pain Sciences, School of Dentistry, Program in 
      Neuroscience, Center to Advance Chronic Pain Research, 12264The University of 
      Maryland, Baltimore, MD, USA.
FAU - Kulkarni, Ashok B
AU  - Kulkarni AB
AUID- ORCID: 0000-0001-9849-3250
AD  - Gene Transfer Core, National Institute of Dental and Craniofacial Research, 
      National Institutes of Health, Bethesda, MD, USA.
AD  - Functional Genomics Section, National Institute of Dental and Craniofacial 
      Research, 2511National Institutes of Health, Bethesda, MD, USA.
LA  - eng
GR  - ZIA DE000664/ImNIH/Intramural NIH HHS/United States
GR  - R35 DE030045/DE/NIDCR NIH HHS/United States
GR  - R01 DE031477/DE/NIDCR NIH HHS/United States
GR  - Z01 DE000664/ImNIH/Intramural NIH HHS/United States
GR  - R01 DE027731/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Mol Pain
JT  - Molecular pain
JID - 101242662
RN  - 0 (TRPV Cation Channels)
RN  - 0 (TRPV1 protein, mouse)
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - EC 2.7.11.22 (Cdk5 protein, mouse)
RN  - S07O44R1ZM (Capsaicin)
SB  - IM
MH  - Animals
MH  - *Capsaicin/pharmacology
MH  - Cyclin-Dependent Kinase 5/genetics/*metabolism
MH  - Ganglia, Spinal/metabolism
MH  - Mice
MH  - Nociception
MH  - Pain/genetics/metabolism
MH  - Phosphorylation
MH  - TRPV Cation Channels/*metabolism
MH  - Threonine/metabolism
PMC - PMC9251968
OTO - NOTNLM
OT  - Cdk5
OT  - TRPV1
OT  - knock-in mouse
OT  - p35
OT  - pain
OT  - phosphorylation
COIS- Declaration of Conflicting Interests: The author(s) declared no potential 
      conflicts of interest with respect to the research, authorship, and/or 
      publication of this article.
EDAT- 2022/06/22 06:00
MHDA- 2022/07/02 06:00
PMCR- 2022/06/29
CRDT- 2022/06/21 04:42
PHST- 2022/06/22 06:00 [pubmed]
PHST- 2022/07/02 06:00 [medline]
PHST- 2022/06/21 04:42 [entrez]
PHST- 2022/06/29 00:00 [pmc-release]
AID - 10.1177_17448069221111473 [pii]
AID - 10.1177/17448069221111473 [doi]
PST - ppublish
SO  - Mol Pain. 2022 Apr;18:17448069221111473. doi: 10.1177/17448069221111473.