Abstract
Whether synaptic transmission is excitatory or inhibitory depends, to a large extent, on whether the ion channels that open upon binding the released neurotransmitter conduct cations or anions. The mechanistic basis of the opposite charge selectivities of Cys-loop receptors has only recently begun to emerge. It is now clear that ionized side chains—whether pore-facing or buried—in the first α-helical turn of the second transmembrane segments underlie this phenomenon and that the electrostatics of backbone atoms are not critically involved. Moreover, on the basis of electrophysiological observations, it has recently been suggested that not only the sign of charged side chains but also their conformation are crucial determinants of cation-anion selectivity. To challenge these ideas with the chemical and structural rigor that electrophysiological observations naturally lack, we performed molecular dynamics, Brownian dynamics, and electrostatics calculations of ion permeation. To this end, we used structural models of the open-channel conformation of the α1 glutamate-gated Cl− channel and the α1 glycine receptor. Our results provided full support to the notion that the conformation of charged sides chains matters for charge selectivity. Indeed, whereas some rotamers of the buried arginines at position 0′ conferred high selectivity for anions, others supported the permeation of cations and anions at similar rates or even allowed the faster permeation of cations. Furthermore, we found that modeling glutamates at position −1′ of the anion-selective α1 glycine receptor open-state structure—instead of the five native alanines—switches charge selectivity also in a conformation-dependent manner, with some glutamate rotamers being much more effective at conferring selectivity for cations than others. Regarding pore size, we found that the mere expansion of the pore has only a minimal impact on cation-anion selectivity. Overall, these results bring to light the previously unappreciated impact of side-chain conformation on charge selectivity in Cys-loop receptors.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.