9.A.14.7.8 Metabotropic glutamate receptor 5, mGluR5, GRM5, of 1212 aas and 7 TMSs. It is a G-protein-coupled receptor for glutamate. Ligand
binding causes a conformation change that triggers signaling via guanine
nucleotide-binding proteins (G proteins) and modulates the activity of
down-stream effectors. Signaling activates a
phosphatidylinositol-calcium second messenger system and generates a
calcium-activated chloride current. GRM5 plays a role in the
regulation of synaptic plasticity and the modulation of the neural
network activity (Minakami et al. 1994). The structure of the transmembrane domain has been determined (Doré et al. 2014). The prevalence, presentation, and progression of Alzheimer's disease (AD)
differ between men and women, although β-amyloid (Aβ) deposition is a
pathological hallmark of AD in both sexes. Aβ-induced activation of the
neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020).
mGluR5 isolated from male mouse cortical and hippocampal
tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from
female mice exhibited no such affinity. This sex-selective Aβ-mGluR5
interaction is not depend on estrogen, but rather Aβ
interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of
autophagy in primary neuronal cultures. Pharmacological inhibition of
mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed
cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female
counterparts. Aβ oligomers also bound with high affinity to human mGluR5
isolated from postmortem donor male cortical brain tissue, but not that
from female samples, suggesting that this mechanism may be relevant to
patients. mGluR5 does not contribute to Aβ
pathology in females, highlighting the complexity of mGluR5 pharmacology
and Aβ signaling that supports the need for sex-specific stratification
in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020).
|
Accession Number: | P41594 |
Protein Name: | Metabotropic glutamate receptor 5 |
Length: | 1212 |
Molecular Weight: | 132469.00 |
Species: | Homo sapiens (Human) [9606] |
Number of TMSs: | 7 |
Location1 / Topology2 / Orientation3: |
Cell membrane1 / Multi-pass membrane protein2 |
Substrate |
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1: MVLLLILSVL LLKEDVRGSA QSSERRVVAH MPGDIIIGAL FSVHHQPTVD KVHERKCGAV
61: REQYGIQRVE AMLHTLERIN SDPTLLPNIT LGCEIRDSCW HSAVALEQSI EFIRDSLISS
121: EEEEGLVRCV DGSSSSFRSK KPIVGVIGPG SSSVAIQVQN LLQLFNIPQI AYSATSMDLS
181: DKTLFKYFMR VVPSDAQQAR AMVDIVKRYN WTYVSAVHTE GNYGESGMEA FKDMSAKEGI
241: CIAHSYKIYS NAGEQSFDKL LKKLTSHLPK ARVVACFCEG MTVRGLLMAM RRLGLAGEFL
301: LLGSDGWADR YDVTDGYQRE AVGGITIKLQ SPDVKWFDDY YLKLRPETNH RNPWFQEFWQ
361: HRFQCRLEGF PQENSKYNKT CNSSLTLKTH HVQDSKMGFV INAIYSMAYG LHNMQMSLCP
421: GYAGLCDAMK PIDGRKLLES LMKTNFTGVS GDTILFDENG DSPGRYEIMN FKEMGKDYFD
481: YINVGSWDNG ELKMDDDEVW SKKSNIIRSV CSEPCEKGQI KVIRKGEVSC CWTCTPCKEN
541: EYVFDEYTCK ACQLGSWPTD DLTGCDLIPV QYLRWGDPEP IAAVVFACLG LLATLFVTVV
601: FIIYRDTPVV KSSSRELCYI ILAGICLGYL CTFCLIAKPK QIYCYLQRIG IGLSPAMSYS
661: ALVTKTNRIA RILAGSKKKI CTKKPRFMSA CAQLVIAFIL ICIQLGIIVA LFIMEPPDIM
721: HDYPSIREVY LICNTTNLGV VTPLGYNGLL ILSCTFYAFK TRNVPANFNE AKYIAFTMYT
781: TCIIWLAFVP IYFGSNYKII TMCFSVSLSA TVALGCMFVP KVYIILAKPE RNVRSAFTTS
841: TVVRMHVGDG KSSSAASRSS SLVNLWKRRG SSGETLRYKD RRLAQHKSEI ECFTPKGSMG
901: NGGRATMSSS NGKSVTWAQN EKSSRGQHLW QRLSIHINKK ENPNQTAVIK PFPKSTESRG
961: LGAGAGAGGS AGGVGATGGA GCAGAGPGGP ESPDAGPKAL YDVAEAEEHF PAPARPRSPS
1021: PISTLSHRAG SASRTDDDVP SLHSEPVARS SSSQGSLMEQ ISSVVTRFTA NISELNSMML
1081: STAAPSPGVG APLCSSYLIP KEIQLPTTMT TFAEIQPLPA IEVTGGAQPA AGAQAAGDAA
1141: RESPAAGPEA AAAKPDLEEL VALTPPSPFR DSVDSGSTTP NSPVSESALC IPSSPKYDTL
1201: IIRDYTQSSS SL