Biology subjects

Rumian, N. L.

Publications and source records attributed to Rumian, N. L..

3 recordsLinked to original sources

bioRxiv2026

CaMKII T286 autophosphorylation is not propagated at basal Ca2+ levels and is required only for the induction phase of LTP

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its autophosphorylation at T286 (P-T286) mediates long-term potentiation (LTP) of synaptic strength. CaMKII forms stable 12-meric holoenzymes, but exchange of its subunits is proposed to propagate the P-T286 state beyond dephosphorylation or degradation of individual subunits. However, a recent study questioned subunit exchange and instead proposed P-T286 propagation by trans-holoenzyme phosphorylation. We show here that both subunit exchange and trans-holoenzyme P-T286 can occur (although cis-holoenzyme P-T286 is much preferred), but that neither mechanism propagates P-T286 at basal cellular Ca2+ levels (50-100 nM) in absence of further Ca2+-stimuli. Functionally, we show that after theta-burst stimulation (TBS), P-T286 is required only during the first minutes of LTP induction that prime for subsequent LTP expression, but neither for LTP expression itself nor for LTP maintenance. These results indicate that P-T286 of CaMKII does not self-perpetuate and does not mediate storage but computation of synaptic information.

neuroscience↗

bioRxiv2023

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory and is neuroprotective in non-rodents

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. This was at [≥]500fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce return of spontaneous circulation. Of additional importance for therapeutic development, cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, even though prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy.

neuroscience↗

bioRxiv2022

Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

neuroscience↗