Correlating structural and energetic changes in glycine receptor activation.

ABSTRACT: Pentameric ligand-gated ion channels (pLGICs) mediate fast chemoelectrical transduction in the nervous system. The mechanism by which the energy of ligand binding leads to current-conducting receptors is poorly understood and may vary among family members. We addressed these questions by correlating the structural and energetic mechanisms by which a naturally occurring M1 domain mutation (?1(Q-26'E)) enhances receptor activation in homo- and heteromeric glycine receptors. We systematically altered the charge of spatially clustered residues at positions 19' and 24', in the M2 and M2-M3 linker domains, respectively, which are known to be critical to efficient receptor activation, on a background of ?1(Q-26'E). Changes in the durations of single receptor activations (clusters) and conductance were used to determine interaction coupling energies, which we correlated with conformational displacements as measured in pLGIC crystal structures. Presence of the ?1(Q-26'E) enhanced cluster durations and reduced channel conductance in homo- and heteromeric receptors. Strong coupling between ?1(-26') and ?1(19') across the subunit interface suggests an important role in receptor activation. A lack of coupling between ?1(-26') and ?1(24') implies that 24' mutations disrupt activation via other interactions. A similar lack of energetic coupling between ?1(-26') and reciprocal mutations in the ? subunit suggests that this subunit remains relatively static during receptor activation. However, the channel effects of ?1(Q-26'E) on ?1? receptors suggests at least one ?1-?1 interface per pentamer. The coupling-energy change between ?1(-26') and ?1(19') correlates with a local structural rearrangement essential for pLGIC activation, implying it comprises a key energetic pathway in activating glycine receptors and other pLGICs.

SUBMITTER: Scott S 

PROVIDER: S-EPMC4342475 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature