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EC coupling
CaV 1.1
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EC coupling research in the Grabner lab - milestones

2013: In vitro expression of β1a3 chimeras in β1-null zebrafish relaxed myotubes revealed a pivotal role of the Src homology 3 (SH3) domain and C terminus of β1a in charge movement restoration. Furthermore, substitution of a P by A in the putative SH3-binding polyproline motif in the proximal C terminus of β1a (also of β2a and β4) fully obstructed α1S charge movement. Consequently, we postulate a model according to which β subunits, probably via the SH3-C-terminal polyproline interaction, adapt a discrete conformation required to modify the β1a conformation apt for voltage sensing in skeletal muscle. (cooperation with Franzini-Armstrong lab).
Dayal et al., 2013, Proc Natl Acad Sci USA

2010: In vivo and in vitro expression of the β1a-specific heptad repeat mutant in β1-null zebrafish relaxed revealed that the C-terminal heptad repeat motif in β1a is not the key determinant of EC coupling, as was postulated earlier by others. With this novel finding, the doors are reopened for in-depth structural-functional studies on the role of the β1a-subunit in skeletal muscle EC coupling. (cooperation with Franzini-Armstrong lab).
Dayal et al., 2010, Cell Calcium

2010: Two distinct DHPR α1S subunits were detected in teleost fish muscle - differentially expressed in slow and fast muscle fibers. Both α1S isoforms did not conduct calcium ions, based on different conductance-blocking mutations, pointing to an evolutionary pressure towards non-calcium-conductivity in fish muscle.
In Science Signaling: EDITORS' CHOICE: N. R. Gough, When a Channel Is Not a Channel. Sci. Signal. 3, ec92 (2010) Schredelseker et al., 2010, Proc Natl Acad Sci USA

2009: Expression of different DHPR β-subunits in β1-null zebrafish relaxed revealed that triad targeting and charge movement restoration can be supported by every of the investigated β-subunits - but that proper tetrad formation and thus full restoration of EC coupling is an exclusive function of the β1a-subunit. (cooperation with Franzini-Armstrong lab).
Schredelseker/Dayal et al., 2009, J. Biol Chem.

2005: Using the newly established model-system of a β1a-null zebrafish strain, the β1a subunit could be identified to be absolutely required for the formation of DHPR tetrads in skeletal muscle and thus for the DHPR-RyR1 protein-protein interaction. (cooperation with Flucher lab and Franzini-Armstrong lab)
Schredelseker et al., 2005, Proc Natl Acad Sci USA

2004: Expression of different DHPR α1 subunit chimeras in α1S-null myotubes and following analysis by immunocytochemistry and freeze-fracture electron microscopy revealed that the α1 II-III linker plays an important role in the formation of tetrads. The organization of DHPRs in tetrads is necessary but not sufficient for skeletal-type EC coupling. (cooperation with Flucher lab and Franzini-Armstrong lab)
Takekura et al., 2004, Mol Biol Cell

2004: Studying the DHPR α1S point mutation R1086H, associated malignant hyperthermia susceptibility, revealed, that this single mutation in the intracellular III-IV linker of the α1S enhances RyR1 sensitivity to activation by both endogenous (voltage sensor) and exogenous (caffeine) activators. (cooperation with Flucher lab and Dirksen lab)
Weiss et al., 2004, Am J Physiol Cell Physiol

2004: Analyzing the critical domain for bidirectional coupling in the DHPR α1S II-III linker on the single amino acid level revealed that the secondary structure of this region is an essential determinant for skeletal-type EC coupling.
Kugler et al., 2004, J Biol Chem

2000: Comparing targeting properties of the skeletal muscle CaV1.1 (α1S) with that of a neuronal isoform CaV2.1 (α1A) and appropriate chimeras revealed that the triad targeting signal of the skeletal muscle channel is located in the α1S C-terminus. (cooperation with Flucher lab)
Flucher et al., 2000, J Cell Biol

1999-2001: Several selected α1 chimeras were used to demonstrate that a critical domain of 45 amino acids in the α1S II-III linker is responsible for the bidirectional crosstalk of the voltage-sensing α1S with the sarcoplasmic Ca2+ release channel RyR1. (cooperation with Beam lab)
Grabner et al., 1999, J Biol Chem
Wilkens et al., 2001, Proc Natl Acad Sci USA
1998: Using N-terminal tagging of L-type and non-L-type α1 subunits with GFP we revealed that L-type channels are clustered into triads, whereas non-L-type channels seem to be diffusely distributed in the surface membrane. Important in later studies: GFP-tagged channels where shown to be fully functional in EC coupling. (cooperation with Beam lab)
Grabner et al., 1998, Proc Natl Acad Sci USA
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