Growth factors differentially regulate neuronal Ca v channels via ERK-dependent signalling

Abstract

Voltage-gated calcium channels (Ca v) are tonically up-regulated via Ras/extracellular signal-regulated kinase (ERK) signalling in sensory neurones. However, the mechanisms underlying the specificity of cellular response to this pathway remain unclear. Neurotrophic factors are attractive candidates to be involved in this process as they are key regulators of ERK signalling and have important roles in neuronal survival, development and plasticity. Here, we report that in rat dorsal root ganglion neurones, endogenous nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and epidermal growth factor (EGF) are all involved in tonic ERK-dependent up-regulation of Ca v channels. Chronic (overnight) deprivation of growth factors inhibits total Ca v current according to developmental changes in expression of the cell surface receptors for NGF, GDNF and EGF. Whilst EGF specifically regulates transcriptional expression of Ca vs, NGF and GDNF also acutely modulate Ca v channels within a rapid (∼10 min) time-frame. These acute effects likely involve changes in the biophysical properties of Ca vs, including altered channel gating rather than changes in surface expression. Furthermore, NGF, GDNF and EGF differentially regulate specific populations of Ca vs. Thus, ERK-dependent regulation of Ca v activity provides an elegant and extremely flexible system with which to tailor calcium influx to discrete functional demands.