Regulation of neuronal high-voltage activated CaV2 Ca2+ channels by the small GTPase RhoA

High-Voltage-Activated (HVA) Ca2+ channels are known regulators of synapse formation and transmission and play fundamental roles in neuronal pathophysiology. Small GTPases of Rho and RGK families, via their action on both cytoskeleton and Ca2+ channels are key molecules for these processes. While the effects of RGK GTPases on neuronal HVA Ca2+ channels have been widely studied, the effects of RhoA on the HVA channels remains however elusive. Using heterologous expression in Xenopus laevis oocytes, we show that RhoA activity reduces Ba2+ currents through CaV2.1, CaV2.2 and CaV2.3 Ca2+ channels independently of CaVβ subunit. This inhibition occurs independently of RGKs activity and without modification of biophysical properties and global level of expression of the channel subunit. Instead, we observed a marked decrease in the number of active channels at the plasma membrane. Pharmacological and expression studies suggest that channel expression at the plasma membrane is impaired via a ROCK-sensitive pathway. Expression of constitutively active RhoA in primary culture of spinal motoneurons also drastically reduced HVA Ca2+ current amplitude. Altogether our data revealed that HVA Ca2+ channels regulation by RhoA might govern synaptic transmission during development and potentially contribute to pathophysiological processes when axon regeneration and growth cone kinetics are impaired.