In a ten-year project, a team from the Karl Landsteiner University of Health Sciences has identified a previously unknown role of calcium channels in the formation of synaptic connections.
Krems (Austria), 30th March 2021 – Components of calcium channels play a decisive role in synapse formation. This is the surprising conclusion of a study comprising more than a decade of research, owing to the involved experimental challenges. The findings were published in PNAS today. The laboratory within the Mental Health & Neuroscience research program at the Karl Landsteiner University of Health Sciences in Krems, Austria (KL Krems) focuses on neuronal functions of regulatory proteins of so-called voltage-gated calcium channels. Over the recent years these proteins – named ?2? – 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.
Nerves are electrified. A lively picture, but given that a flow of ions actually transmits nerve signals not far from reality. The transmission of signals between nerve cells depends on voltage-gated calcium channels. These channels trigger the release of neurotransmitters at synapses (the connections between neurons), and hence modulate higher brain functions such as learning and memory. ?2? proteins are regulatory components of calcium channels and also serve as targets for gabapentin, a drug used to treat epilepsy and neuropathic pain. However, for specific reasons, unravelling the synaptic functions of these proteins has proven extremely difficult. In a project comprising ten years of research, a team headed by Prof. Gerald Obermair, head of the division physiology at KL Krems has now identified within the Mental Health & Neuroscience research program a surprising and fundamental novel function of this protein.
Knockout in Three Steps
The state-of-the-art method for characterising proteins involves “knocking out” the protein’s gene and then analysing the consequence on various cell functions. However, three different types of ?2? proteins exist in the brain – and each of these three isoforms can, to some extent, compensate the loss of the others. This fact caused the major experimental challenge, as Prof. Obermair explains: “Each isoform is encoded by its own gene. If we knock out one of them, the other proteins step in as replacements, at least to some degree. So, we had to come up with an experimental model in which none of the three genes are expressed.” This turned out to be a huge experimental challenge, with a success rate of less than 5%. After overcoming this hurdle, though, the team made unique novel discoveries.
“Our findings allow a surprising conclusion: presynaptic ?2? proteins are absolutely essential for the formation of excitatory synapses,” summarizes Prof. Obermair the outcome of years of research which was initiated at the Medical University of Innsbruck, Austria. “This new role of ?2? proteins goes way beyond the regulation of cellular calcium currents.” Recent publications by Obermair’s team (e.g. in the Journal of Neuroscience – see below) and also by others already proposed a “trans-synaptic” function of ?2? proteins, however, the novel fundamental role was not immediately obvious. But, in the course of many experiments, partly in collaboration with other international laboratories, as for example the research group headed by Prof. Ryuichi Shigemoto at the Institute of Science and Technology Austria, a conclusive picture gradually emerged.
Specific roles of ?2? proteins
The experiments revealed that without ?2? 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 ?2? 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 ?2? 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 ?2? proteins in organising excitatory synapses.
“The role of ?2? proteins in the formation and differentiation of connections between nerve cells is remarkable,” Prof. Obermair emphasises once more. “The study influences our basic understanding of the formation of synaptic connections. Indeed, it even suggests that ?2? could be the nucleation point around which synapses are organised.” The present findings will contribute to the future understanding of the protein’s role in the clinical manifestation of neurological and neuropsychiatric disorders and thereby help translating these ground-breaking basic-research findings into added value for patients.
Images available on request
Presynaptic ?2? subunits are key organizers of glutamatergic synapses. C. L. Schöpf, C. Ablinger, S. M. Geisler, R. I. Stanika, M. Campiglio, W. A. Kaufmann, B. Nimmervoll, B. Schlick, J. Brockhaus, M. Missler, R. Shigemoto & G. J. Obermair. Ref. DOI: 10.1073/pnas.1920827118
Presynaptic ?2?-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring. Geisler S, Schöpf CL, Stanika R, Kalb M, Campiglio M, Repetto D, Traxler L, Missler M, Obermair GJ. J Neurosci. 2019, 39:2581-2605. doi: 10.1523/JNEUROSCI.2234-18.2019.
About Karl Landsteiner University of Health Sciences
Karl Landsteiner University of Health Sciences (KL) is a pioneer for innovation in medical, psychological and health sciences education and research, and a catalyst for groundbreaking work which will benefit society at large. KL offers an interdisciplinary and internationally aligned study programme in human medicine and psychology. Research at KL focuses on niche fields in bridge disciplines such as biomedical engineering, psychology and psychodynamics, mental health & neuroscience as well as topics including water quality and related health issues. A network of university hospitals in St. Pölten, Krems, and Tulln provides students with quality-assured, research-led education; it. It enables them to do top-class clinical and translational research that is recognised worldwide. Karl Landsteiner University received accreditation by the Agency for Quality Assurance and Accreditation Austria (AQ Austria) in 2013.
Prof. Dr. Gerald Obermair
Dept. Pharmacology, Physiology & Microbiology
Research Program Mental Health & Neuroscience
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