Disease-associated mutations of α2δ proteins affect calcium channels and channel-independent synaptic functions

α2δ proteins serve as auxiliary subunits of voltage-gated calcium channels and regulate channel membrane expression and biophysical current properties. Besides their channel-function, α2δ proteins regulate synapse formation, differentiation, and synaptic wiring. Considering these important functions, it is not surprising that CACNA2D1-4, the genes encoding for α2δ-1 to -4 isoforms, have been implicated in neurological, neurodevelopmental, and neuropsychiatric disorders. However, how mutations in α2δ proteins can lead to brain disorders is insufficiently understood. By analyzing mutations linked to autism spectrum disorder (α2δ-1 and α2δ-3) and epileptic encephalopathy and cerebellar atrophy (α2δ-2) we show that, besides altering calcium channel functions, dysfunctional α2δ proteins can affect synapse differentiation, trans-synaptic signaling, as well as pre- and postsynaptic functions. Moreover, a recently identified mutation in α2δ-2 dissociates trans-synaptic signaling from calcium channels, proving that this function does not involve the calcium channel complex. Taken together, our data strongly link the human mutations to the underlying brain disorders and highlight the importance of studying α2δ mutations not only in the context of channelopathies but also synaptopathies.