Nordman_2014_FASEB.J_28_2995

The alpha7 nicotinic receptor (alpha7) 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 alpha7 that directs the growth of neurites in developing neural cells. Now we show that choline activation of alpha7 promotes a rise in intracellular calcium from local ER stores via Galphaq signaling, leading to IP3 receptor (IP3R) activation at the growth cone of differentiating PC12 cells. A mutant alpha7 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 alpha7 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 alpha7 channel and activation of the Galphaq pathway are necessary for growth. Taken together, the findings reveal an inhibitory mechanism of alpha7 on cytoskeletal growth via the intracellular calcium activity of the receptor channel and the Galphaq signaling pathway at the growth cone.-Nordman, J. C., Kabbani, N. Microtubule dynamics at the growth cone are mediated by alpha7 nicotinic receptor activation of a Galphaq and IP3 receptor pathway.