SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB1 receptors

Abstract

Background and Purpose: Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid CB1 receptors. SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB1 receptors co-localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of activated CB1 receptors in transfected heterologous cells. Consequently, the transient association of CB1 receptors with β-arrestin2 is enhanced and prolonged, and CB1 receptor-mediated ERK1/2 signalling is decreased. Because of these actions, SGIP1 may modulate affect, anxiety, pain processing, and other physiological processes controlled by the endocannabinoid system (ECS). Experimental Approach: Using a battery of behavioural tests, we investigated the consequences of SGIP1 deletion in tasks regulated by the ECS in SGIP1 constitutive knockout (SGIP1−/−) mice. Key Results: In SGIP1−/− mice, sensorimotor gating, exploratory levels, and working memory are unaltered. SGIP1−/− mice have decreased anxiety-like behaviours. Fear extinction to tone is facilitated in SGIP1−/− females. Several cannabinoid tetrad behaviours are altered in the absence of SGIP1. SGIP1−/− males exhibit abnormal behaviours on Δ9-tetrahydrocannabinol withdrawal. SGIP1 deletion also reduces acute nociception, and SGIP1−/− mice are more sensitive to analgesics. Conclusion and Implications: SGIP1 was detected as a novel protein associated with CB1 receptors, and profoundly modified CB1 receptor signalling. Genetic deletion of SGIP1 particularly affected behavioural tests of mood-related assessment and the cannabinoid tetrad. SGIP1−/− mice exhibit decreased nociception and augmented responses to CB1 receptor agonists and morphine. These in vivo findings suggest that SGIP1 is a novel modulator of CB1 receptor-mediated behaviour.