SGIP1 is involved in regulation of emotionality, mood, and nociception and tunes in vivo signaling of Cannabinoid Receptor 1.

BACKGROUND AND PURPOSE: Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid receptor 1 (CB1R). SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB1R co-localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of activated CB1R in transfected heterologous cells; as a consequence, the transient association of the CB1R with beta-arrestin2 is enhanced and prolonged, and CB1-mediated ERK1/2 signaling 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 behavioral tests, we investigated the consequences of SGIP1 deletion in tasks regulated by the ECS in SGIP1 constitutive knock-out (SGIP1-/- ) mice.

KEY RESULTS: In SGIP1-/- mice, sensorimotor gating, exploratory levels and working memory are unaltered. SGIP1-/- mice have decreased anxiety-like behaviors. Fear extinction to tone, is facilitated in SGIP1-/- females. Several cannabinoid tetrad behaviors are altered in the absence of SGIP1. SGIP1-/- males exhibit abnormal THC withdrawal behaviors. SGIP1 deletion also reduces acute nociception, and SGIP1-/- mice are more sensitive to analgesics.

CONCLUSION AND IMPLICATIONS: SGIP1 was detected as a novel associated molecule with the CB1R. This relationship results in profound modification of CB1R signaling. Genetic deletion of SGIP1 has refined physiological consequences apparent in behavioral tests of mood-related assessment and the cannabinoid tetrad. SGIP1-/- mice have decreased nociception and augmented responses to CB1R agonists and morphine. These in vivo findings suggest SGIP1 is a novel modulator of CB1R-related behavior.