Components of calcium channels play a decisive role in the formation of excitatory synapses, according to the findings of researchers from the Mental Health & Neuroscience research programme at the Karl Landsteiner University of Health Sciences in Krems, Austria (KL Krems).
α2δ proteins, which regulate the so-called voltage-gated calcium channels, have emerged as important regulators of synaptic transmission between nerve cells. The present finding of these proteins critically regulating the formation of excitatory synapses in the central nervous system, however, came as a surprise, said the authors of the study published in PNAS recently.
“Our findings allow a surprising conclusion: presynaptic α2δ proteins are absolutely essential for the formation of excitatory synapses,” said Prof. Gerald Obermair, head of the division physiology at KL Krems and the team head, in a statement. “This new role of α2δ proteins goes way beyond the regulation of cellular calcium currents.”
However, three different types of α2δ proteins exist in the brain – and each of these three isoforms can, to some extent, compensate for the loss of the others. This fact caused the major experimental challenge. Each isoform is encoded by its own gene. If one of the genes is knocked out, the other proteins step in as replacements, at least to some degree. So, the researchers had to come up with an experimental model in which none of the three genes is expressed, Prof. Obermair explains.
The experiments revealed that without α2δ proteins, synapses of cultured nerve cells are unable to release neurotransmitters; moreover, they also lack the calcium channels as well as critical components of synaptic neurotransmitter vesicles. This causes an insufficient differentiation of nerve endings and subsequently a reduction of glutamate receptors on postsynaptic nerve cells. Together this suggests that α2δ proteins organise the bridging between the two sides of synapses.
Finally, genetic cell therapy was employed to demonstrate that each one of the three types of α2δ proteins found in the brain was able to restore synapse formation and synaptic function, underlining the central position of these proteins. Taken together, the experiments revealed the critical role of α2δ protein organising excitatory synapses.
Components of calcium channels also serve as targets for gabapentin, a drug used to treat epilepsy and neuropathic pain.