Nicotinic Acid Adenine Dinucleotide Phosphate Potentiates Neurite Outgrowth*

Abstract

Ca²⁺ regulates a spectrum of cellular processes including many aspects of neuronal function. Ca²⁺-sensitive events such as neurite extension and axonal guidance are driven by Ca²⁺ signals that are precisely organized in both time and space. These complex cues result from both Ca²⁺ influx across the plasma membrane and the mobilization of intracellular Ca²⁺ stores. In the present study, using rat cortical neurons, we have examined the effects of the novel intracellular Ca²⁺-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) on neurite length and cytosolic Ca²⁺ levels. We show that NAADP potentiates neurite extension in response to serum and nerve growth factor and stimulates increases in cytosolic Ca²⁺ from bafilomycin-sensitive Ca²⁺ stores. Simultaneous blockade of inositol trisphosphate and ryanodine receptors abolished the effects of NAADP on neurite length and reduced the magnitude of NAADP-mediated Ca²⁺ signals. This is the first report demonstrating functional NAADP receptors in a mammalian neuron. Interplay between NAADP receptors and more established intracellular Ca²⁺ channels may therefore play important signaling roles in the nervous system.