Microtubule dynamics at the growth cone are mediated by α7 nicotinic receptor activation of a Gαq and IP3 receptor pathway.

ABSTRACT

The α7 nicotinic receptor (α7) plays an important role in neuronal growth and structural plasticity in the developing brain. We have recently characterized a G-protein-signaling pathway regulated by α7 that directs the growth of neurites in developing neural cells. Now we show that choline activation of α7 promotes a rise in intracellular calcium from local ER stores via Gαq signaling, leading to IP3 receptor (IP3R) activation at the growth cone of differentiating PC12 cells. A mutant α7 significantly attenuated in calcium conductance (D44A; P<0.001) was found to be unable to promote IP3R signaling and calcium store release. In addition, calcium elevation via α7 correlates with a significant attenuation in the rate of microtubule invasion of the growth cone (P<0.001). This process was also attenuated in the D44A mutant and blocked by an inhibitor of the IP3R, suggesting that calcium flow through the α7 channel and activation of the Gαq pathway are necessary for growth. Taken together, the findings reveal an inhibitory mechanism of α7 on cytoskeletal growth via the intracellular calcium activity of the receptor channel and the Gαq signaling pathway at the growth cone.-Nordman, J. C., Kabbani, N. Microtubule dynamics at the growth cone are mediated by α7 nicotinic receptor activation of a Gαq and IP3 receptor pathway.