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

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 mGlu_8a 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.