Benefit or Harm? How Cholesterol Affects the Nerve Cells

The nicotinic acetylcholine (cholinergic) receptor (nAChR) is a non-specific ion channel (Na + / K +), activation of which occurs as a result of binding of different ligand molecules. This protein plays a central role in many nervous and muscular processes. His name is due to the ability to selectively bind a nicotine molecule. Disruption of the work of this receptor is associated with the development of many neurological diseases (epilepsy, schizophrenia, Parkinson’s and Alzheimer’s, etc.), as well as alcohol, nicotine and cocaine addictions. In addition, the action of general anesthetics is associated with nAChR. It is not surprising that the spatial organization of the receptor causes increased interest. At the moment, the researchers have the structure nAChR from the “battery” of the electric ramp ( Torpedo ), obtained by high-resolution electron microscopy (EM, see also[2] ). According to these data, the channel is geteropentamer formed in several different subunits (? ? , ?, ?, ? ? and ?). Interestingly, in the areas of contact between subunits forming the receptor, numerous cavities are observed, the role of which has not yet been established.

Cholesterol harm help

Researchers from the Center for Molecular Modeling at the University of Pennsylvania, after analyzing numerous experimental data, concluded that cholesterol should play an important role in the spatial organization of nAChR [1] . Moreover, if earlier such a role was seen in the creation of a specific lipid environment of the channel in the membrane (“cholesterol coat”), then, in this case, a hypothesis was put forward that cholesterol can be directly inserted between the subunits of nAChR.

Several modern methods of molecular modeling were used to test this hypothesis: missing loop fragments in the EM structure of the protein were completed with the help of homology modeling (see also [3] ), the finding of cholesterol binding sites was produced by docking algorithms (see also [ 4] ), optimization of the obtained structure of the nAChR complex with embedded molecules of cholesterol placed in the lipid bilayer (cell membrane model) was performed during molecular dynamics calculations (MD, see also [5] ). This system had more than 200 thousand atoms, so the resource-intensive MD calculations were performed using a supercomputer cluster.

As a result, it was shown that this receptor is capable of binding 15 molecules of cholesterol that fill specific cavities between its subunits. In this case, the size and geometry of such cavities provide specific binding of cholesterol, and not other components of membranes (for example, phospholipids). Interestingly, the specific incorporation of cholesterol into nAChR stabilizes the receptor structure: in the absence of cholesterol, the structure collapses rapidly in the MD process and loses the characteristic folding necessary for the formation of the pore-conducting channel. At the same time, in complex with cholesterol, the structure of the receptor remains close to the experimental one during the entire model experiment.

Thus, in the channel function nAChR (and in general – the conduction of a nerve impulse), cholesterol can play an unexpectedly important role. This feature, according to the authors, should be inherent in other related nAChR receptors, among which such important molecules as the receptors of serotonin and GABA. While in the confirmation of their hypothesis, researchers have only indirect experimental data, as well as modeling results. The final verdict, apparently, can be carried out when it will be possible to obtain the crystallographic structure of the cholinergic receptor complex with cholesterol.

Reference:

  1. Brannigan G., Hénin J., Law R., Eckenhoff R., Klein ML (2008). Embedded cholesterol in the nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA 105, 14418-23
  2. Channel eukaryotic chaperonin opening like the diaphragm of the camera ;
  3. The triumph of computer methods: prediction of the structure of proteins ;
  4. Drag-design: how in the modern world are new drugs created ;
  5. Molecular dynamics of biomolecules. Part I. History of half a century ago.
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