Swapping the I-II intracellular linker between L-type CaV1.2 and R-type CaV2.3 high-voltage gated calcium channels exchanges activation attributes

• Published in: Channels (Austin, Tex.) Vol. 4; no. 1; pp. 42 - 50
• Main Authors: Gonzalez-Gutierrez, Giovanni, Miranda-Laferte, Erick, Contreras, Gustavo, Neely, Alan, Hidalgo, Patricia
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2010
• Subjects: Amino Acid Sequence; Animals; Binding; Biology; Bioscience; Calcium; Calcium - metabolism; Calcium Channels, L-Type - chemistry; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Calcium Channels, R-Type - chemistry; Calcium Channels, R-Type - genetics; Calcium Channels, R-Type - metabolism; Cancer; Cation Transport Proteins - chemistry; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell; Cycle; Ion Channel Gating; Landes; Membrane Potentials; Molecular Sequence Data; Oocytes; Organogenesis; Protein Conformation; Protein Structure, Tertiary; Proteins; Rabbits; Rats; Structure-Activity Relationship; Time Factors; Xenopus laevis
• ISSN: 1933-6950; 1933-6969
• DOI: 10.4161/chan.4.1.10562

Calcium entry through voltage-gated calcium channels (VGCC) initiates diverse cellular functions. VGCC pore-forming subunit (Ca V α1) contains four homology repeats, each encompassing a voltage sensor and a pore domain. Three main classes of Ca V α1 subunits have been described, Ca V 1, Ca V 2 and Ca V 3 that differ in their voltage-dependence of activation and in the extent in which this process is modulated by the auxiliary β-subunit (Ca V β). Association of Ca V β induces a coil-to-helix conformation of the I-II intracellular linker joining the first and second repeat of CaVα1 that is thought to be crucial for modulation of channel function. When expressed in Xenopus laevis oocytes in the absence of Ca V β the voltage to reach 50% activation (V 0.5 ) for Ca V 1.2 and Ca V 2.3 differs by more than 60 mV and the channel current-carrying capacity by more than thirty-fold. Here we report that the difference in V 0.5 is reduced to about 30 mV and the current-carrying capacity becomes virtually identical when the I-II linkers of Ca V 1.2 and Ca V 2.3 are swapped. Co-expression with Ca V β increases the current-carrying capacity of chimeric channels by the same extent, while the difference in V 0.5 with respect to their corresponding parental channels vanishes. Our findings indicate that Ca V β modulatory potency is determined by both, the nature of the I-II linker and the pore-forming subunit background. Moreover, they demonstrate that the I-II linker encodes self-reliant molecular determinants for channel activation and suggest that besides to the secondary structure adopted by this segment upon Ca V β association, its chemical nature is as well relevant.