Regulation of neurite outgrowth by Gi/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 Gproteins 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 proper central 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. KeywordsG-protein; Neurite Outgrowth; Cell Signaling; Cannabinoid Receptor; Neurodegeneration; Review INTRODUCTIONNeuronal differentiation is a complex process that integrates many signals to drive electrophysiological, morphological, and transcriptional changes (1,2,3,4). This process is characterized by the initial formation of immature neurites, commonly referred to as "neurite outgrowth." The neurites then further develop into a single axon and multiple dendrites, followed by maturation of the neuron and the formation of dendritic spines (1). Many signals at the cell surface are integrated to shape axonal and dendritic outgrowths as well as their directionality and maturation (5,6,7,8). Not surprisingly, neurite outgrowth is precisely regulated due to its importance in the proper development of the organism. During neurite outgrowth, signals at the membrane are transduced to a large repertoire of enzymes to ultimately trigger changes in gene transcription in the nucleus. In addition, the signals produce vast changes in the actin and microtubule cytoskeletal networks in order to generate and stabilize the growing neurites (1,8 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptA diverse array of ligands including neurotrophins, cytokines, hormones, and neurotransmitters can stimulate neurite outgrowth upon binding to their cognate receptors (5,7,9,10,11,12,13,14). Heterotrimeric guanine nucleotide-binding proteins (G-proteins) are one of the most widely used signal transduction systems in mammals, and signaling through the G i/o family of G-proteins regulates neurite outgrowth. In cortical neurons, dopaminemediated stimulation of the D2 dopamine receptor can induce axonal neurite elongation (10). Similarl...

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