Dataset Information

Anesthetic effects on the structure and dynamics of the second transmembrane domains of nAChR alpha4beta2.

ABSTRACT: Channel functions of the neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR), one of the most widely expressed subtypes in the brain, can be inhibited by volatile anesthetics. Our Na(+) flux experiments confirmed that the second transmembrane domains (TM2) of alpha4 and beta2 in 2:3 stoichiometry, (alpha4)(2)(beta2)(3), could form pentameric channels, whereas the alpha4 TM2 alone could not. The structure, topology, and dynamics of the alpha4 TM2 and (alpha4)(2)(beta2)(3) TM2 in magnetically aligned phospholipid bicelles were investigated using solid-state NMR spectroscopy in the absence and presence of halothane and isoflurane, two clinically used volatile anesthetics. (2)H NMR demonstrated that anesthetics increased lipid conformational heterogeneity. Such anesthetic effects on lipids became more profound in the presence of transmembrane proteins. PISEMA experiments on the selectively (15)N-labeled alpha4 TM2 showed that the TM2 formed transmembrane helices with tilt angles of 12 degrees +/-1 degrees and 16 degrees +/-1 degrees relative to the bicelle normal for the alpha4 and (alpha4)(2)(beta2)(3) samples, respectively. Anesthetics changed the tilt angle of the alpha4 TM2 from 12 degrees +/-1 degrees to 14 degrees +/-1 degrees , but had only a subtle effect on the tilt angle of the (alpha4)(2)(beta2)(3) TM2. A small degree of wobbling motion of the helix axis occurred in the (alpha4)(2)(beta2)(3) TM2. In addition, a subset of the (alpha4)(2)(beta2)(3) TM2 exhibited counterclockwise rotational motion around the helix axis on a time scale slower than 10(-4) s in the presence of anesthetics. Both helical tilting and rotational motions have been identified computationally as critical elements for ion channel functions. This study suggested that anesthetics could alter these motions to modulate channel functions.

SUBMITTER: Cui T

PROVIDER: S-EPMC2812609 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anesthetic effects on the structure and dynamics of the second transmembrane domains of nAChR alpha4beta2.

Cui Tanxing T Canlas Christian G CG Xu Yan Y Tang Pei P

Biochimica et biophysica acta 20090826 2

Channel functions of the neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR), one of the most widely expressed subtypes in the brain, can be inhibited by volatile anesthetics. Our Na(+) flux experiments confirmed that the second transmembrane domains (TM2) of alpha4 and beta2 in 2:3 stoichiometry, (alpha4)(2)(beta2)(3), could form pentameric channels, whereas the alpha4 TM2 alone could not. The structure, topology, and dynamics of the alpha4 TM2 and (alpha4)(2)(beta2)(3) TM2 in magneti ...[more]

PMID: 19715664

Similar Datasets

Project description:Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel alpha4beta2 nAChR by over 10 ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1 (Haddadian et al., J. Phys. Chem. B 2008, 112, 13981). On average there were 65 and 74 interfacial lipids around the closed- and open-channel alpha4beta2 nAChR, respectively, in the equilibrated simulation systems. In the open-channel system, 42% of the interfacial POPA had acyl chains partially inserted into intra- or intersubunit cavities, as compared to only 7% in the closed-channel alpha4beta2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller headgroup, POPA could access some nonannular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA acted not only as an acceptor for hydrogen bonding (H bonding) as POPC did, but also as a donor through its hydroxyl group for H bonding with the backbone of the protein. The charged headgroup of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the alpha4beta2. A higher number of salt bridges and hydrogen bonds (H bonds) between POPA and the alpha4beta2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR.

Dataset Information

Anesthetic effects on the structure and dynamics of the second transmembrane domains of nAChR alpha4beta2.

Publications

Anesthetic effects on the structure and dynamics of the second transmembrane domains of nAChR alpha4beta2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets