Familial Hemiplegic Migraine Type 1 Mutations K1336E, W1684R, and V1696I Alter Ca sub(v)2.1 Ca super(2+) Channel Gating: Evidence for beta-Subunit Isoform-Specific Effects

• Published in: The Journal of biological chemistry 2004-12, Vol.279 (50), p.51844-51850
• Main Authors: Muellner, Carmen, Broos, Ludo AM, Van Den Maagdenberg, Arn MJM, Striessnig, Joerg
• Format: Article
• Language: English
• Subjects: Xenopus
• ISSN: 0021-9258; 1083-351X

Mutations in the Ca sub(v)2.1 alpha1-subunit of P/Q-type Ca super(2+)channels cause human diseases, including familial hemiplegic migraine type-1 (FHM1). FHM1 mutations alter channel gating and enhanced channel activity at negative potentials appears to be a common pathogenetic mechanism. Different beta-subunit isoforms (primarily beta sub(4) and beta sub(3)) participate in the formation of Ca sub(v)2.1 channel complexes in mammalian brain. Here we investigated not only whether FHM1 mutations K1336E (KE), W1684R (WR), and V1696I (VI) can affect Ca sub(v)2.1 channel function but focused on the important question whether mutation-induced changes on channel gating depend on the beta-subunit isoform. Mutants were co-expressed in Xenopus oocytes together with beta sub(1), beta sub(3), or beta sub(4) and alpha sub(2)delta sub(1) subunits, and channel function was analyzed using the two-electrode voltage-clamp technique. WR shifted the voltage dependence for steady-state inactivation of Ba super(2+) inward currents (I sub(Ba)) to more negative voltages with all beta-subunits tested. In contrast, a similar shift was observed for KE only when expressed with beta sub(3). All mutations promoted I sub(Ba) decay during pulse trains only when expressed with beta sub(1) or beta sub(3) but not with beta sub(4). Enhanced decay could be explained by delayed recovery from inactivation. KE accelerated I sub(Ba) inactivation only when co- expressed with beta sub(3), and VI slowed inactivation only with beta sub(1) or beta sub(3). KE and WR shifted channel activation of I sub(Ba) to more negative voltages. As the beta-subunit composition of Ca sub(v)2.1 channels varies in different brain regions, our data predict that the functional FHM1 phenotype also varies between different neurons or even within different neuronal compartments.