Alpha 7 nicotinic receptors attenuate neurite development through calcium activation of calpain at the growth cone.

ABSTRACT: The ?7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel that plays an important role in cellular calcium signaling contributing to synaptic development and plasticity, and is a key drug target for the treatment of neurodegenerative conditions such as Alzheimer's disease. Here we show that ?7 nAChR mediated calcium signals in differentiating PC12 cells activate the proteolytic enzyme calpain leading to spectrin breakdown, microtubule retraction, and attenuation in neurite growth. Imaging in growth cones confirms that ?7 activation decreases EB3 comet motility in a calcium dependent manner as demonstrated by the ability of ?7 nAChR, ryanodine, or IP3 receptor antagonists to block the effect of ?7 nAChR on growth. ?7 nAChR mediated EB3 comet motility, spectrin breakdown, and neurite growth was also inhibited by the addition of the selective calpain blocker calpeptin and attenuated by the expression of an ?7 subunit unable to bind G?q and activate calcium store release. The findings indicate that ?7 nAChRs regulate cytoskeletal dynamics through local calcium signals for calpain protease activity.

SUBMITTER: King JR 

PROVIDER: S-EPMC5955587 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature