Neurotrophin-4 Modulates The Mechanotransducer Ca(V)3.2 T-Type Calcium Current In Mice Down-Hair Neurons

The T-type Ca2+ channel Ca(v)3.2 is expressed in nociceptive and mechanosensitive sensory neurons. The mechanosensitive D-hair (down-hair) neurons, which innervate hair follicles, are characterized by a large-amplitude Ca(v)3.2 T-current involved in the amplification of slow-moving stimuli. The molecules and signalling pathways that regulate T-current expression in mechanoreceptors are unknown. In the present study, we investigated the effects of NT-4 (neurotrophin-4) on Ca(v)3.2 T-current expression in D-hair neurons in vitro. Interruption of the supply of NT-4 with peripheral nerve axotomy induced a non-transcriptional decrease in the T-current amplitude of fluoro-gold-labelled axotomized sensory neurons. The T-current amplitude was restored by incubation with NT-4. Deletion of NT-4 through genetic ablation resulted in a similar selective loss of the large-amplitude T-current in NT-4(-/-) sensory neurons, which was rescued by the addition of NT-4. NT-4 had no effect on the T-current in Ca(v)3.2(-/-) D-hair neurons. Neither the biophysical properties of the T-current nor the transcript expression of Ca(v)3.2 were modified by NT-4. Pharmacological screening of signalling pathways activated under the high-affinity NT-4 receptor TrkB (tropomyosin receptor kinase B) identified a role for PI3K (phosphoinositide 3-kinase) in the potentiation of T-current. The results of the present study demonstrate the post-transcriptional up-regulation of the Ca(v)3.2 T-current through TrkB activation and identify NT-4 as a target-derived factor that regulates the mechanosensitive function of D-hair neurons through expression of the T-current.