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1.
J Neurochem ; 127(2): 199-208, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23895321

RESUMO

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.


Assuntos
Fatores de Despolimerização de Actina/fisiologia , Galanina/farmacologia , Neuritos/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Animais , Western Blotting , Ativação Enzimática/efeitos dos fármacos , Feminino , Gânglios Espinais/citologia , Cones de Crescimento/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microscopia de Vídeo , Células PC12 , Pseudópodes/efeitos dos fármacos , Ratos , Estimulação Química , Proteínas rac de Ligação ao GTP/metabolismo
2.
Proc Natl Acad Sci U S A ; 100(10): 6180-5, 2003 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-12721371

RESUMO

The neuropeptide galanin is expressed in the dorsal root ganglia (DRG) and spinal cord and is thought to be involved in the modulation of pain processing. However, its mechanisms of action are complex and poorly understood, as both facilitatory and inhibitory effects have been described. To understand further the role played by galanin in nociception, we have generated two transgenic lines that overexpress galanin in specific populations of primary afferent DRG neurons in either an inducible or constitutive manner. In the first line, a previously defined enhancer region from the galanin locus was used to target galanin to the DRG (Gal-OE). Transgene expression recapitulates the spatial endogenous galanin distribution pattern in DRG neurons and markedly overexpresses the peptide in the DRG after nerve injury but not in the uninjured state. In the second line, an enhancer region of the c-Ret gene was used to constitutively and ectopically target galanin overexpression to the DRG (Ret-OE). The expression of this second transgene does not alter significantly after nerve injury. Here, we report that intact Ret-OE, but not Gal-OE, animals have significantly elevated mechanical and thermal thresholds. After nerve damage, using a spared nerve-injury model, mechanical allodynia is attenuated markedly in both the Gal-OE and Ret-OE mice compared with WT controls. These results support an inhibitory role for galanin in the modulation of nociception both in intact animals and in neuropathic pain states.


Assuntos
Galanina/genética , Galanina/fisiologia , Gânglios Espinais/fisiologia , Neurônios/fisiologia , Limiar da Dor/fisiologia , Dor/prevenção & controle , Animais , Gânglios Espinais/lesões , Gânglios Espinais/fisiopatologia , Camundongos , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Dor/fisiopatologia , Fatores de Tempo
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