Analysis of the expression of the nicotinic acetylcholine receptor type α7 (shown in green) and Lypd6 (shown in red) in hippocampal neurons by confocal microscopy. The nucleus of the neuron is shown in blue (stained with Hoechst 33342). Scale 10 μm
Russian researchers were able to find a protein that inhibits acetylcholine receptors in the human brain. It turned out to be a three-loop protein, the Lypd6 protein. Additional study of its properties may lead to the discovery of pharmacological applications of this modulator. The researchers' article was published in the journal Frontiers in Cell And Development Biology.
Many receptors in the central nervous system have associated regulatory proteins expressed in specific neurons (Maher et al., 2017). Ancillary regulatory proteins have been described for the AMPA, NMDA, GABAA and ACh receptors. For example, the GPI-anchored protein Lynx1, which belongs to the Ly6 / uPAR family of three-finger proteins, interacts with the α7-type nicotinic acetylcholine receptor (α7-nAChR) and co-localizes with it in areas of the brain important for learning and memory, and is critical for neuronal loss. plasticity during brain development after birth.
In addition, Lypd6 is the so-called GPI-anchored protein of the Ly6 / uPAR family, expressed in the brain. Previously, several scientific laboratories have received data indicating that Lypd6 interacts with nAChR and may be involved in the transmission of cholinergic signals in the central nervous system. However, the specificity of the neuromodulator and the direction of modulation of nicotinic receptors (positive or negative) remained unexplored.
The researchers from the Institute of Bioorganic Chemistry, RAS, together with the staff of the Scientific Center of Neurology and the University of Leuven, for the first time studied the pharmacological spectrum of action of Lypd6, identified subtypes of nAChR, the targets of this neuromodulator, and determined the concentrations at which this neuromodulator specifically inhibits nAChR α7 and α3β4 types. Co-localization of Lypd6 with α7-nAChR was shown in neurons of the cortex and hippocampus.
In addition, for the first time, the authors were able to observe in neurons the colocalization of a member of the Ly6 / uPAR family with nAChR of the α3β4 type, which indicates that this subtype of nicotinic receptor may also possess auxiliary regulatory proteins.
The addition of the recombinant Lypd6 preparation to the medium bathing the surviving rat hippocampal slices significantly inhibited the choline-induced current on the α7-nAChR. In addition, like the three-finger α-bungarotoxin (the strongest neurotoxin from the venom of the Bungarus multicinctus snake, acting on α7-nAChR), Lypd6 inhibited long-term potentiation in the surviving sections of the hippocampus of mice, which means a negative effect on synaptic plasticity. These data indicate that Lypd6 suppresses the function of nicotinic acetylcholine receptors in the brain, as well as processes associated with their work.
Computer modeling of the interaction of Lypd6 with α7-nAChR predicted the binding site of the neuromodulator to the receptor. Comparative analysis of the interaction of Lynx1 and Lypd6 with the receptor made it possible to explain the positive and negative modulation of the receptor by these neuromodulators. Verification of the predicted site by site-directed mutagenesis with subsequent analysis of the activity of the resulting Lypd6 mutants will fill in the existing gaps in the description of the mechanisms underlying the regulation of nicotinic acetylcholine receptors.
The results obtained allow us to consider Lypd6 as an endogenous negative neuromodulator of the cholinergic system of the brain. At the same time, positive modulation of α7-nAChR by another neuromodulator, Lynx1, has been repeatedly shown earlier. Possibly, Lynx1 and Lypd6, both co-localized with α7-nAChR on neuronal membranes, represent a pair of positive and negative neuromodulators required to fine-tune cholinergic signaling in the brain. The positive and negative effects on synaptic plasticity imply that Lynx1 and Lypd6 may also modulate the processes involved in memory and learning in different ways.
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