SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB1 receptors
Abstrakt
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 beta-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 Delta(9)-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.