Regulation of neurite outgrowth by G(i/o) signaling pathways

Abstract

Neurogenesis is a long and winding journey. A neural progenitor cell migrates long distances, differentiates by forming a single axon and multiple dendrites, undergoes maturation, and ultimately survives. The initial formation of neurites during neuronal differentiation, commonly referred to as "neurite outgrowth," can be induced by a large repertoire of signals that stimulate an array of receptors and downstream signaling pathways. The G(i/o) family of heterotrimeric G-proteins are abundantly expressed in the brain and enriched at neuronal growth cones. Recent evidence has uncovered several G(i/o)-coupled receptors that induce neurite outgrowth and has begun to elucidate the underlying molecular mechanisms. Emerging data suggests that signals from several G(i/o)-coupled receptors converge at the transcription factor STAT3 to regulate neurite outgrowth and at Rac1 and Cdc42 to regulate cytoskeletal reorganization. Physiologically, signaling through G(i/o)-coupled cannabinoid receptors is critical for pro percentral nervous system development. As the mechanisms by which G(i/o)-coupled receptors regulate neurite outgrowth are clarified, it is becoming evident that modulating signals from G(i/o) and their receptors has great potential for the treatment of neurodegenerative diseases.

Figure 1

Heterotrimeric G-protein mechanism. The activation of the G-protein coupled receptor by a ligand (L) causes the exchange of GDP for GTP on the α subunit. This switches Gα to the active conformation and results in the release of Gα and Gβγ from the receptor to signal to downstream effectors. The switch is turned off by the intrinsic GTP hydrolysis (GTPase) activity of Gα, which leads to its reassociation with Gβγ and the receptor. The regulators of G-protein signaling (RGS) play key roles in inactivating G-protein signaling. The activators of G-protein signaling (AGS) activate G-proteins by several mechanisms.

Figure 2

Effector pathways activated by G_i/o signaling. Signals from a wide array of hormones, neurotransmitters, and chemokines are transduced into intracellular responses by G_i/o-coupled receptors. Depicted are pathways that are stimulated by Gα and Gβγ and lead to changes in gene expression and cytoskeletal reorganization. See text for further details. GIRK, G-protein-coupled inward rectifying potassium channels.

Figure 3

G_i/o signaling to the nucleus during the induction of neurite outgrowth. Signal flow emanating from stimulation of the G_i/o-coupled cannabinoid receptor 1 (CB1R) to the activation of the transcription factor STAT3 is depicted in the schematic. It is likely that Gβγ also signals to downstream effectors to change patterns of gene expression, possibly through p42/44 mitogen activated protein kinase (MAPK). See text for further details. pY, phospho-tyrosine; pS, phospho-serine.

Figure 4

G_i/o signaling to the actin cytoskeleton during the induction of neurite outgrowth. Signaling from the G_i/o-coupled CB1R to its effectors GRIN, Cdc42 and Rac1 and their potential downstream targets is shown in the schematic. The intermediate molecules between CB1R and Rac1 have been omitted for clarity. It is likely that Gβγ also signals to yet to be identified downstream effectors to reorganize the actin cytoskeleton. Known interactions are depicted by solid arrows, putative interactions by dashed arrows. See text for further details. PAK, p21-activated kinase; SSH, Slingshot; WASP, Wiskott-Aldrich-syndrome protein.