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Microtubule dynamics at the growth cone are mediated by ?7 nicotinic receptor activation of a G?q and IP3 receptor pathway.

ABSTRACT: The ?7 nicotinic receptor (?7) 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 ?7 that directs the growth of neurites in developing neural cells. Now we show that choline activation of ?7 promotes a rise in intracellular calcium from local ER stores via G?q signaling, leading to IP3 receptor (IP3R) activation at the growth cone of differentiating PC12 cells. A mutant ?7 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 ?7 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 ?7 channel and activation of the G?q pathway are necessary for growth. Taken together, the findings reveal an inhibitory mechanism of ?7 on cytoskeletal growth via the intracellular calcium activity of the receptor channel and the G?q signaling pathway at the growth cone.-Nordman, J. C., Kabbani, N. Microtubule dynamics at the growth cone are mediated by ?7 nicotinic receptor activation of a G?q and IP3 receptor pathway.

SUBMITTER: Nordman JC

PROVIDER: S-EPMC4062821 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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

Nordman Jacob C JC Kabbani Nadine N

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140331 7

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 signifi ...[more]

PMID: 24687992

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Project description:BackgroundMicrotubule (MT) regulators play essential roles in multiple aspects of neural development. In vitro reconstitution assays have established that the XMAP215/Dis1/TOG family of MT regulators function as MT 'plus-end-tracking proteins' (+TIPs) that act as processive polymerases to drive MT growth in all eukaryotes, but few studies have examined their functions in vivo. In this study, we use quantitative analysis of high-resolution live imaging to examine the function of XMAP215 in embryonic Xenopus laevis neurons.ResultsHere, we show that XMAP215 is required for persistent axon outgrowth in vivo and ex vivo by preventing actomyosin-mediated axon retraction. Moreover, we discover that the effect of XMAP215 function on MT behavior depends on cell type and context. While partial knockdown leads to slower MT plus-end velocities in most cell types, it results in a surprising increase in MT plus-end velocities selective to growth cones. We investigate this further by using MT speckle microscopy to determine that differences in overall MT translocation are a major contributor of the velocity change within the growth cone. We also find that growth cone MT trajectories in the XMAP215 knockdown (KD) lack the constrained co-linearity that normally results from MT-F-actin interactions.ConclusionsCollectively, our findings reveal unexpected functions for XMAP215 in axon outgrowth and growth cone MT dynamics. Not only does XMAP215 balance actomyosin-mediated axon retraction, but it also affects growth cone MT translocation rates and MT trajectory colinearity, all of which depend on regulated linkages to F-actin. Thus, our analysis suggests that XMAP215 functions as more than a simple MT polymerase, and that in both axon and growth cone, XMAP215 contributes to the coupling between MTs and F-actin. This indicates that the function and regulation of XMAP215 may be significantly more complicated than previously appreciated, and points to the importance of future investigations of XMAP215 function during MT and F-actin interactions.

Dataset Information

Microtubule dynamics at the growth cone are mediated by ?7 nicotinic receptor activation of a G?q and IP3 receptor pathway.

Publications

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

Similar Datasets

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