Galanin stimulates neurite outgrowth from sensory neurons by inhibition of Cdc42 and Rho GTPases and activation of cofilin

Abstract

We and others have previously shown that the neuropeptide galanin modulates neurite outgrowth from adult sensory neurons via activation of the second galanin receptor; however, the intracellular signalling pathways that mediate this neuritogenic effect have yet to be elucidated. Here, we demonstrate that galanin decreases the activation state in adult sensory neurons and PC12 cells of Rho and Cdc42 GTPases, both known regulators of filopodial and growth cone motility. Consistent with this, activated levels of Rho and Cdc42 levels are increased in the dorsal root ganglion of adult galanin knockout animals compared with wildtype controls. Furthermore, galanin markedly increases the activation state of cofilin, a downstream effector of many of the small GTPases, in the cell bodies and growth cones of sensory neurons and in PC12 cells. We also demonstrate a reduction in the activation of cofilin, and alteration in growth cone motility, in cultured galanin knockout neurons compared with wildtype controls. These data provide the first evidence that galanin regulates the Rho family of GTPases and cofilin to stimulate growth cone dynamics and neurite outgrowth in sensory neurons. These findings have important therapeutic implications for the treatment of peripheral sensory neuropathies.

Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla

“…Galanin is involved in diverse physiological functions, including nociception, arousal/sleep regulation, cognition, and many aspects of neuroendocrine activities that are associated with feeding, energy metabolism, thermoregulation, osmotic and water balance, and reproduction (Mechenthaler, 2008). A recent publication by Hobson and colleagues using differentiated PC12 cells suggests a role of galanin in neurite outgrowth (Hobson et al, 2013). We observed a high abundance of galanin/pepcan colocalization in the cell bodies of the LC, as well as in many of the axonal projections, throughout the brain and those descending to the spinal cord.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…GAL 2 predominantly couples to a G q/11 -type G protein, leading to phospholipase C activation, which stimulates Ca 2+ release via inositol phosphate hydrolysis and opens Ca 2+ -dependent ion channels in a PTXresistant manner, in both GAL 2 -transfected cell lines (Smith et al, 1997b;Borowsky et al, 1998;Fathi et al, 1998;Pang et al, 1998;Wang et al, 1998c) and GAL 2 -expressing rat microglial cells (Ifuku et al, 2011). GAL 2 activation led to a decrease in both Rho and Cdc42 GTPase activity and activation of cofilin in rat PC12 pheochromocytoma cells (Hobson et al, 2013). In SCLC cells, another signaling pathway has been proposed for GAL 2 involving functional coupling to a G 12/13 -type G protein and subsequent activation of the small GTPase protein Rho A (Wittau et al, 2000).…”

“…An early study reported that treatment with galanin failed to induce neurite outgrowth in PC12 cells (Klimaschewski et al, 1995), whereas a more recent study demonstrated that galanin significantly increased the percentage of PC12 cells Galanin Family Peptides and Receptors exhibiting neurite outgrowth (Hawes et al, 2006;Hobson et al, 2013).…”

“…This is confirmed by the finding that GAL 2 -KO mice have a one-third reduction in neurite outgrowth consistent with that observed in galanin-KO mice (Hobson et al, 2006), which cannot be rescued by the addition of galanin or galanin (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Most recently, Hobson et al (2013) showed that, in adult sensory neurons and PC12 cells, galanin decreases the activation state of Rho and Cdc42 GTPases, both known regulators of filopodial and growth cone motility. Consistent with this, the levels of activated Rho and Cdc42 are increased in the DRG of galanin-KO mice compared with WT controls.…”

Galanin receptors as a potential target for neurological disease

“…This can lead to downstream PI3K-dependent phosphorylation of protein kinase B that results in the inhibition of caspase 3 and caspase 9 activity [34,73,74]. Activation of the G q protein coupled GalR2 receptor has been shown to stimulate the Rho family of GTPases [75]. GalR2 activates both the G 12 protein and signals through the G 12 /Rho pathway and subsequently activates the small GTPase protein Rho A in small cell lung cancer cells [34,76].…”