A schistosome [beta] subunit remodels inactivation of a calcium channel _via_ an N-terminal polyacidic motif

The beta subunit of high voltage-activated Ca (Cav) channels targets the pore forming [alpha]~1~ subunit to the plasma membrane and defines the biophysical phenotype of the Cav channel complex. Cav channel inactivation following activation and opening is tightly regulated and is an essential property that not only prevents excessive entry of Ca^2+^ into the cell but may also have functions in signal transduction. The [beta] subunit modulates Ca^2+^-dependent and voltage-dependent components of Cav channel inactivation via its interaction with the I-II linker of the [alpha]~1~ subunit. Here, using Cav2.3 and whole-cell patch-clamp, we show that a [beta] subunit from the human parasite _Schistosoma mansoni_ ([beta]~Sm~) accelerates inactivation via a unique, long N-terminal polyacidic motif (NPAM). The accelerating effect of NPAM-containing subunits, both native ([beta]~Sm~)and chimeric mammalian [beta]~1b~, [beta]~2a~ and [beta]~3~ subunits to which NPAM had been attached, was only apparent when Ca^2+^ was internally buffered with BAPTA (5 mM) or when Ba^2+^ was used as the charge carrier, two commonly used strategies to eliminate Ca^2+^/calmodulin dependent inactivation. These results indicate that calmodulin is not involved. In addition to accelerating inactivation, NPAM-containing [beta] subunits significantly reduced current density with respect to their non NPAM-bearing counterparts. Interestingly, when the amino acids N terminal to NPAM were deleted, inactivation of Cav2.3 currents was faster than in the presence of the entire N-terminal portion of the [beta]~Sm~ subunit, as if the pre-NPAM region counteracts the effect of NPAM. Presence of NPAM also resulted in currents that activated faster, suggesting that NPAM increases open channel probability. However, NPAM does not modulate inactivation gating. In summary, this study identifies a structural determinant of Cav channel inactivation that is entirely unlike those previously known