Essential Role Of TRPC Channels In The Guidance Of Nerve Growth Cones By Brain-derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is known to promote neuronal survival and differentiation and to guide axon extension in vitro and in vivo. The BDNF-induced chemoattraction of axonal growth cones requires Ca2+ signaling, but how Ca2+ at the growth cone is regulated by BDNF remains largely unclear. Extracellular application of BDNF triggers membrane currents resembling that through TRPC (Transient Receptor Potential Canonical) channels in rat pontine neurons and in Xenopus spinal neurons. We here report that in cultured cerebellar granule cells TRPC channels contribute to the BDNF-induced Ca2+ elevation at the growth cone and are required for BDNF-induced chemoattractive turning. Several members of the TRPC family are highly expressed in these neurons, and both Ca2+ elevation and growth cone turning induced by BDNF were abolished by pharmacological inhibition of TRPC channels, over-expression of a dominant negative form of TRPC3 or TRPC6, or down-regulation of the expression of TRPC3 with small interference RNA (siRNA). Thus TRPC channel activity is essential for nerve growth cone guidance by BDNF.