Collaborative research published in PNAS focuses on skeletal muscle cell understanding
Joint efforts between research teams at UW and PNNL have resulted in the publication of an article entitled "Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle" appearing in the April 5, 2005 issue of the Proceedings of the National Academy of Sciences.
This article describes new findings regarding the regulation mechanisms of the Cav1.1 calcium channel in skeletal muscle, which permits the slow influx of calcium ions into the myocyte that initiates muscle contraction. The regulation of this channel is impaired in dystrophic mouse muscle, suggesting that dysfunction of this channel may be important in neuromuscular disease. The Cav channel is highly regulated by interactions with multiple proteins that ensure the precise coordination of contractile function under various cellular conditions. This fine-tuning of channel function during contraction requires that many of these regulatory proteins reside in proximity to their regulation sites within the channel. In fact, the Cav channel functions as a multi-protein complex for which the composite proteins are just beginning to be defined.
With the PNAS paper, the UW-PNNL research teams have demonstrated a novel regulatory aspect of this channel complex; that is, that a 40-amino acid peptide at the C-terminus of the channel itself is proteolytically cleaved in vivo to provide a regulatory interaction with the major portion of the channel. Interaction of the channel with this truncated peptide is essential to the subsequent formation of protein-protein interactions with additional regulatory proteins. The definition of the precise cleavage site, which was accomplished by mass spectrometric analysis by the PNNL team, was critical to understanding the exact nature and significance of this truncation. As the related Cav1.2 channel in the heart and brain also undergoes a C-terminal cleavage, this mechanism likely has wider significance in similar regulation of cardiac contractility and neural transmission.
PNNL scientists Marina Gritsenko, David Camp, and Diana Bigelow were among the co-authors, who included University of Washington scientists Joanne Hulme, Keiichi Konoki, Teddy Lin, and William Catterall.
The work was supported by PNNL's Biomolecular Systems Initiative and National Center for Research Resources, the Muscular Dystrophy Association, the National Institutes of Health, and the American Heart Association. A PDF of the article is available at http://www.pnas.org/cgi/reprint/102/14/5274.pdf.