Molecular determinant for specific Ca/Ba selectivity profiles of low and high threshold Ca2+ channels.
Résumé
Voltage-gated Ca(2+) channels (VGCC) play a key role in many physiological functions by their high selectivity for Ca(2+) over other divalent and monovalent cations in physiological situations. Divalent/monovalent selection is shared by all VGCC and is satisfactorily explained by the existence, within the pore, of a set of four conserved glutamate/aspartate residues (EEEE locus) coordinating Ca(2+) ions. This locus however does not explain either the choice of Ca(2+) among other divalent cations or the specific conductances encountered in the different VGCC. Our systematic analysis of high- and low-threshold VGCC currents in the presence of Ca(2+) and Ba(2+) reveals highly specific selectivity profiles. Sequence analysis, molecular modeling, and mutational studies identify a set of nonconserved charged residues responsible for these profiles. In HVA (high voltage activated) channels, mutations of this set modify divalent cation selectivity and channel conductance without change in divalent/monovalent selection, activation, inactivation, and kinetics properties. The Ca(V)2.1 selectivity profile is transferred to Ca(V)2.3 when exchanging their residues at this location. Numerical simulations suggest modification in an external Ca(2+) binding site in the channel pore directly involved in the choice of Ca(2+), among other divalent physiological cations, as the main permeant cation for VGCC. In LVA (low voltage activated) channels, this locus (called DCS for divalent cation selectivity) also influences divalent cation selection, but our results suggest the existence of additional determinants to fully recapitulate all the differences encountered among LVA channels. These data therefore attribute to the DCS a unique role in the specific shaping of the Ca(2+) influx between the different HVA channels.
Fichier principal
Cens_GP-200709771.pdf (257.58 Ko)
Télécharger le fichier
Cens_etal_JGP_suppdata.pdf (148.07 Ko)
Télécharger le fichier
cens_fig1.tif (73.94 Ko)
Télécharger le fichier
cens_fig2.tif (227.23 Ko)
Télécharger le fichier
cens_fig3.tif (85.7 Ko)
Télécharger le fichier
cens_fig4.tif (71.56 Ko)
Télécharger le fichier
cens_fig5.tif (23.61 Ko)
Télécharger le fichier
cens_fig6.tif (57.22 Ko)
Télécharger le fichier
cens_fig7.tif (154.06 Ko)
Télécharger le fichier
cens_suppfig1.tif (123.22 Ko)
Télécharger le fichier
cens_suppfig2.tif (134.87 Ko)
Télécharger le fichier
cens_suppfig3.tif (72.08 Ko)
Télécharger le fichier
cens_suppfig4.tif (94.33 Ko)
Télécharger le fichier
| Origine | Fichiers produits par l'(les) auteur(s) |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|
| Format | Autre |
|---|