Abstract
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.
Highlights
Cellular signaling via the CB1 cannabinoid receptor has been predicated upon the understanding that ∆9 -tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, and that ∆9 -THC analogs serve as agonists to promote G protein activation
In addition to G proteins, the CB1 receptor interacts with β-arrestins, which serve as regulators of cellular signaling or receptor trafficking [6,7]
Our understanding of functional modulation of the CB1 receptor by Cannabinoid receptor interacting protein 1a (CRIP1a) has implicated of functional modulation of the CB(Gi3, 1 receptor by CRIP1a has implicated
Summary
Cellular signaling via the CB1 cannabinoid receptor has been predicated upon the understanding that ∆9 -tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis (reviewed in [1]), and that ∆9 -THC analogs serve as agonists to promote G protein activation. Cannabinoid receptor interacting protein 1a (CRIP1a) was sought and discovered as a result of findings by the Deborah Lewis laboratory that deletion of the distal C-terminal amino acids augmented the CB1 receptor constitutive inhibition of the voltage-dependent Ca2+ current in superior cervical ganglion neurons, suggesting that the distal C-terminal domain performed an inhibitory function [8,9]. Reasoning that the C-terminal binds to a regulatory protein, the Lewis laboratory performed a yeast two-hybrid screen which identified CRIP1a as a key CB1 receptor-associated protein [9,10] They demonstrated that heterologous expression of CRIP1a could attenuate constitutive inhibition of N-type Ca2+ channels by exogenously expressed CB1 receptors in superior cervical ganglion neurons [10]. Regulation of CB1 receptor activity by CRIP1a can be investigated at both the functional and structural levels with the goal of designing peptide or small molecule drugs that can selectively target the CRIP1a-CB1 receptor interaction for therapeutic intervention in the treatment of pain, convulsions [11,12,13,14], schizophrenia [15,16], and neurodegenerative motor disorders [17]
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