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Background  The Ca v β subunits of high voltage-activated Ca 2+  channels control the trafficking and biophysical properties of the α 1  subunit. The Ca v β-α 1  interaction site has been mapped by crystallographic studies. Nevertheless, how this interaction leads to channel regulation has not been determined. One hypothesis is that βs regulate channel gating by modulating movements of IS6. A key requirement for this direct-coupling model is that the linker connecting IS6 to the α-interaction domain (AID) be a rigid structure.    Methodology/Principal Findings  The present study tests this hypothesis by altering the flexibility and orientation of this region in α 1 2.2, then testing for Ca v β regulation using whole cell patch clamp electrophysiology. Flexibility was induced by replacement of the middle six amino acids of the IS6-AID linker with glycine (PG6). This mutation abolished β2a and β3 subunits ability to shift the voltage dependence of activation and inactivation, and the ability of β2a to produce non-inactivating currents. Orientation of Ca v β with respect to α 1 2.2 was altered by deletion of 1, 2, or 3 amino acids from the IS6-AID linker (Bdel1, Bdel2, Bdel3, respectively). Again, the ability of Ca v β subunits to regulate these biophysical properties were totally abolished in the Bdel1 and Bdel3 mutants. Functional regulation by Ca v β subunits was rescued in the Bdel2 mutant, indicating that this part of the linker forms β-sheet. The orientation of β with respect to α was confirmed by the bimolecular fluorescence complementation assay.    Conclusions/Significance  These results show that the orientation of the Ca v β subunit relative to the α 1 2.2 subunit is critical, and suggests additional points of contact between these subunits are required for Ca v β to regulate channel activity.

Orientation of the Calcium Channel β Relative to the α12.2 Subunit Is Critical for Its Regulation of Channel Activity