title: Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus.
abstract: The cannabinoid type 1 receptor (Cnr1, CB1R) mediates a plethora of physiological functions in the central nervous system as a presynaptic modulator of neurotransmitter release. The recently identified cannabinoid receptor-interacting protein 1a (Cnrip1a, CRIP1a) binds to the C-terminal domain of CB1R, a region known to be important for receptor desensitization and internalization. Evidence that CRIP1a and CB1R interact in vivo has been reported, but the neuroanatomical distribution of CRIP1a is unknown. Moreover, while alterations of hippocampal CRIP1a levels following limbic seizures indicate a role in controlling excessive neuronal activity, the physiological function of CRIP1a in vivo has not been investigated. In this study, we analyzed the spatial distribution of CRIP1a in the hippocampus and examined CRIP1a as a potential modulator of CB1R signaling. We found that Cnrip1a mRNA is co-expressed with Cnr1 mRNA in pyramidal neurons and interneurons of the hippocampal formation. CRIP1a protein profiles were largely segregated from CB1R profiles in mossy cell terminals but not in hippocampal CA1 region. CB1R activation induced relocalization to close proximity with CRIP1a. Adeno-associated virus-mediated overexpression of CRIP1a specifically in the hippocampus revealed that CRIP1a modulates CB1R activity by enhancing cannabinoid-induced G protein activation. CRIP1a overexpression extended the depression of excitatory currents by cannabinoids in pyramidal neurons of the hippocampus and diminished the severity of chemically induced acute epileptiform seizures. Collectively, our data indicate that CRIP1a enhances hippocampal CB1R signaling in vivo.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Guggenhuber
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 1:A1, 17177, Stockholm, Sweden.|Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
authors.forename: Alan
authors.initials: A
authors.lastname: Alpar
authors.affiliation: Institute of Physiology, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Chen
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schmitz
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wickert
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Mattheus
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.|Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, UNSW, High Street, Randwick, Sydney, NSW, 2052, Australia.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Harasta
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Purrio
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kaiser
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK.
authors.forename: Maurice R
authors.initials: MR
authors.lastname: Elphick
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.affiliation: Institute of Physiology, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kilb
authors.affiliation: Institute of Physiology, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany.
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Luhmann
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 1:A1, 17177, Stockholm, Sweden.|Department of Molecular Neuroscience, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany. blutz@uni-mainz.de.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany. m.klugmann@unsw.edu.au.|Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, UNSW, High Street, Randwick, Sydney, NSW, 2052, Australia. m.klugmann@unsw.edu.au.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives; D019706:Excitatory Postsynaptic Potentials; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017966:Pyramidal Cells / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: C000602666:CRIP1a protein, mouse; D002352:Carrier Proteins; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C062018:HU 211; D007608:Kainic Acid
keywords: AAV; CB1R; CRIP1a; Cannabinoid receptor; Cannabinoid receptor-interacting protein 1a; Hippocampus; Seizures