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Carnitine palmitoyltransferase 1C negatively regulates the endocannabinoid hydrolase ABHD6 in mice, depending on nutritional status
- Source :
- British Journal of Pharmacology, British Journal of Pharmacology, Wiley, 2021, 178 (7), pp.1507-1523. ⟨10.1111/bph.15377⟩, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Background and Purpose The enzyme α/β‐hydrolase domain containing 6 (ABHD6), a new member of the endocannabinoid system, is a promising therapeutic target against neuronal‐related diseases. However, how ABHD6 activity is regulated is not known. ABHD6 coexists in protein complexes with the brain‐specific carnitine palmitoyltransferase 1C (CPT1C). CPT1C is involved in neuro‐metabolic functions, depending on brain malonyl–CoA levels. Our aim was to study CPT1C–ABHD6 interaction and determine whether CPT1C is a key regulator of ABHD6 activity depending on nutritional status. Experimental Approach Co‐immunoprecipitation and FRET assays were used to explore ABHD6 interaction with CPT1C or modified malonyl–CoA‐insensitive or C‐terminal truncated CPT1C forms. Cannabinoid CB1 receptor‐mediated signalling was investigated by determining cAMP levels. A novel highly sensitive fluorescent method was optimized to measure ABHD6 activity in non‐neuronal and neuronal cells and in brain tissues from wild‐type (WT) and CPT1C–KO mice. Key Results CPT1C interacted with ABHD6 and negatively regulated its hydrolase activity, thereby regulating 2‐AG downstream signalling. Accordingly, brain tissues of CPT1C–KO mice showed increased ABHD6 activity. CPT1C malonyl–CoA sensing was key to the regulatory role on ABHD6 activity and CB1 receptor signalling. Fasting, which attenuates brain malonyl–CoA, significantly increased ABHD6 activity in hypothalamus from WT, but not CPT1C–KO, mice. Conclusions and Implications Our finding that negative regulation of ABHD6 activity, particularly in the hypothalamus, is sensitive to nutritional status throws new light on the characterization and the importance of the proteins involved as potential targets against diseases affecting the CNS.<br />We thank Dr. Gemma Fabriàs and Alexandre García from the Research Unit of BioActive Molecules (Institut de Química Avançada de Catalunya, IQAC) for technical assistance in the analysis of endocannabinoid levels. We also thank Prof. Kenneth Mackie from the Department of Psychological and Brain Sciences, Indiana University Bloomington (USA), for providing ABHD6 antibody for western blotting assays in brain tissue. This work was supported by the Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017‐83813‐C3‐3‐R to N.C. and R.R.‐R.), Joint Bilateral Project Japan‐Spain/AEI (PCI2018‐092997/AEI to R.R.‐R.) and Fundació La Marató de TV3 (Grant 87/C/2016 to N.C.). A.F. and C.R. are recipients of a fellowship from the Agència de Gestió d'Ajuts Universitaris i de la Recerca (AGAUR) in Catalonia.
- Subjects :
- 0301 basic medicine
Cannabinoid receptor
Enzimas
Ratones
Hydrolases
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
medicine.medical_treatment
Regulator
Neurones
Neuronas
Hippocampus
Mice
chemistry.chemical_compound
0302 clinical medicine
malonyl-CoA
CPT1C
Ratolins
Cervell
Neurons
Hipotàlem
Chemistry
Brain
Fasting
ABHD6
Endocannabinoid system
Enzymes
Cell biology
Malonyl Coenzyme A
Nutrición
Hypothalamus
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Proteínas
malonyl–CoA
Cerebro
Nutritional Status
03 medical and health sciences
Hydrolase
medicine
Animals
Endocannabinoid signalling
Nutrició
Nutrition
Pharmacology
Carnitine O-Palmitoyltransferase
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Proteins
Monoacylglycerol Lipases
030104 developmental biology
Malonyl-CoA
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Cannabinoid
Enzims
Proteïnes
Hipotálamo
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14765381 and 00071188
- Volume :
- 178
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....f56e410962420854a178a006b0527494