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Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure

1
Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA
2
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA
3
Center for Molecular Signaling, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USA
4
Department of Physiology and Pharmacology, Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(20), 3672; https://doi.org/10.3390/molecules24203672
Received: 17 September 2019 / Revised: 1 October 2019 / Accepted: 8 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue Cannabinoids)
Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB1 cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB1-mediated N-type Ca2+ currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB1 receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3′,5′monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation. These studies indicated that CRIP1a attenuates the G protein signaling cascade through modulating which Gi/o subtypes interact with the CB1 receptor. CRIP1a also attenuates CB1 receptor internalization via β-arrestin, suggesting that CRIP1a competes for β-arrestin binding to the CB1 receptor. Predictions of CRIP1a secondary structure suggest that residues 34-110 are minimally necessary for association with key amino acids within the distal C-terminus of the CB1 receptor, as well as the mGlu8a metabotropic glutamate receptor. These interactions are disrupted through phosphorylation of serines and threonines in these regions. Through investigations of the function and structure of CRIP1a, new pharmacotherapies based upon the CRIP-CB1 receptor interaction can be designed to treat diseases such as epilepsy, motor dysfunctions and schizophrenia. View Full-Text
Keywords: adenylyl cyclase; β-arrestin; computational chemistry; CP55940; cyclic adenosine 3′,5′monophosphate (cAMP); extracellular signal-regulated kinase (ERK); G proteins; G protein coupled receptor (GPCR); WIN55212-2 adenylyl cyclase; β-arrestin; computational chemistry; CP55940; cyclic adenosine 3′,5′monophosphate (cAMP); extracellular signal-regulated kinase (ERK); G proteins; G protein coupled receptor (GPCR); WIN55212-2
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MDPI and ACS Style

Booth, W.T.; Walker, N.B.; Lowther, W.T.; Howlett, A.C. Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure. Molecules 2019, 24, 3672.

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