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Structure paper

TitleStructural bases for stoichiometry-selective calcium potentiation of a neuronal nicotinic receptor.
Journal, issue, pagesBr J Pharmacol, Vol. 181, Issue 13, Page 1973-1992, Year 2024
Publish dateMar 7, 2024
AuthorsSimone Mazzaferro / Guipeun Kang / Kathiresan Natarajan / Ryan E Hibbs / Steven M Sine /
PubMed AbstractBACKGROUND AND PURPOSE: α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin ...BACKGROUND AND PURPOSE: α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin potentiation are not known.
EXPERIMENTAL APPROACH: To identify calcium binding sites, we applied cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulations to each stoichiometric form of the α4β2 nACh receptor in the presence of calcium ions. To test whether the identified calcium sites are linked to potentiation, we generated mutants of anionic residues at the sites, expressed wild type and mutant receptors in clonal mammalian fibroblasts, and recorded ACh-elicited single-channel currents with or without calcium.
KEY RESULTS: Both cryo-EM and MD simulations show calcium bound to a site between the extracellular and transmembrane domains of each α4 subunit (ECD-TMD site). Substituting alanine for anionic residues at the ECD-TMD site abolishes stoichiometry-selective calcium potentiation, as monitored by single-channel patch clamp electrophysiology. Additionally, MD simulation reveals calcium association at subunit interfaces within the extracellular domain. Substituting alanine for anionic residues at the ECD sites reduces or abolishes stoichiometry-selective calcium potentiation.
CONCLUSIONS AND IMPLICATIONS: Stoichiometry-selective calcium potentiation of the α4β2 nACh receptor is achieved by calcium association with topographically distinct sites framed by anionic residues within the α4 subunit and between the α4 and β2 subunits. Stoichiometry-selective calcium potentiation could result from the greater number of calcium sites in the stoichiometric form with three rather than two α4 subunits. The results are relevant to modulation of signalling via α4β2 nACh receptors in physiological and pathophysiological conditions.
External linksBr J Pharmacol / PubMed:38454578
MethodsEM (single particle)
Resolution2.35 - 3.41 Å
Structure data

40752

8ssz

EMDB-40752, PDB-8ssz:
The 2alpha3beta stoichiometry of full-length human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine and calcium
Method: EM (single particle) / Resolution: 2.64 Å

40753

8st0

EMDB-40753, PDB-8st0:
The 2alpha3beta stoichiometry of full-length human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine
Method: EM (single particle) / Resolution: 2.4 Å

40754

8st1

EMDB-40754, PDB-8st1:
The 3alpha2beta stoichiometry of human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine and calcium
Method: EM (single particle) / Resolution: 3.41 Å

40755

8st2

EMDB-40755, PDB-8st2:
The 3alpha2beta stoichiometry of human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine
Method: EM (single particle) / Resolution: 2.94 Å

40756

8st3

EMDB-40756, PDB-8st3:
The 2alpha3beta stoichiometry of human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine and calcium
Method: EM (single particle) / Resolution: 2.93 Å

40757

8st4

EMDB-40757, PDB-8st4:
The 2alpha3beta stoichiometry of human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine
Method: EM (single particle) / Resolution: 2.35 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM

ChemComp-CA:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-OCT:
N-OCTANE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / cys-loop ligand-gated pentameric ion channels / cation-selective channel / acetylcholine / calcium

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