Disentangling the Switching Behaviour of Membrane Receptors

Molecular receptors in membranes control many processes in living cells and are also used as targets for drugs. Membrane receptors are activated by the binding of messenger substances known as ligands. Many membrane receptors are made up of different subunits, each of which can bind a ligand. This makes the activation mechanism complex.

In a recent publication in Proceedings of the National Academy of Sciences, entitled “Thermodynamic profile of mutual subunit control in a heteromeric receptor” (DOI: 10.1073/pnas.2100469118), a team of scientists including Prof. Holger Gohlke from JSC at Forschungszentrum Jülich and Heinrich Heine University Düsseldorf, Prof. Klaus Benndorf from Jena University Hospital, and Prof. Eckhard Schulz from Schmalkalden University of Applied Sciences carried out a very original functional analysis of the switching behaviour of the tetrameric CNG channel, which is involved in olfaction. The channel consists of four subunits that the authors concatenated, resulting in 12 configurations with permutated subunit order. Gohlke’s group helped to develop an understanding of the most likely spatial subunit arrangement with molecular simulations. The energetic interaction of the various subunits at these receptors was precisely described using site-directed mutagenesis, functional electrical measurement, and mathematical analysis with complex Markov models.

The strategy described in the publication is also suitable for analysing other membrane receptors, which allows information to be gleaned on how ligands, including drugs, can switch such receptors on or off. The work was funded within DFG Research Group 2518, "Functional dynamics of ion channels and transporters – DynIon".

Contact: Prof. Holger Gohlke, h.gohlke@fz-juelich.de

from JSC News Nr. 283, 24 September 2021