James D. Fessenden, Ph.D.
Research Scientist
Ryanodine receptor structure-function
Email: fessenden at bbri.org

Research Summary
A key triggering step in striated muscle contraction is the release of Ca2+ from intracellular stores via activation of the ryanodine receptor (RyR).  The activity of this Ca2+ release channel is regulated by numerous associated proteins and pharmacological compounds.  We have previously characterized a molecular interaction site of 4-chloro-m-cresol (4-CmC), a potent RyR activator used for clinical diagnosis of the skeletal muscle disorder, malignant hyperthermia (MH).  Our long-term goal is to use 4-CmC to covalently attach conformationally-sensitive fluorescent probes to the RyR in order to define the dynamic structural changes of the RyR that occur during channel opening.  Using fluorescence resonance energy transfer (FRET) methods, we will eventually measure physical distances between defined locations on the RyR and its associated proteins (see figure).

Diagram depicting the ryanodine receptor (RyR) and its associated proteins.

Selected Publications
Laver DR, Hamada T, Fessenden JD, Ikemoto N. The ryanodine receptor pore blocker neomycin also inhibits channel activity via a previously undescribed high-affinity Ca(2+) binding site. J Membr Biol. 2007 Dec;220(1-3):11-20.

Fessenden JD, Feng W, Pessah IN, Allen PD. Amino acid residues Gln4020 and Lys4021 of the ryanodine receptor type 1 are required for activation by 4-chloro-m-cresol. J Biol Chem. 2006 Jul 28;281(30):21022-31.

Jacobson AR, Moe ST, Allen PD, Fessenden JD. Structural determinants of 4-chloro-m-cresol required for activation of ryanodine receptor type 1. Mol Pharmacol. 2006 Jul;70(1):259-66.

Cherednichenko G, Hurne AM, Fessenden JD, Lee EH, Allen PD, Beam KG, Pessah
IN. Conformational activation of Ca2+ entry by depolarization of skeletal myotubes.
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15793-8.

Fessenden JD, Feng W, Pessah IN, Allen PD. Mutational analysis of putative calcium binding motifs within the skeletal ryanodine receptor isoform, RyR1. J Biol Chem. 2004 Dec 17;279(51):53028-35.

Paolini C, Fessenden JD, Pessah IN, Franzini-Armstrong C. Evidence for conformational coupling between two calcium channels. Proc Natl Acad Sci U S A. (2004) 101(34):12748-52.

Fessenden, J. D., Perez, C. F., Goth, S., Pessah, I. N., and Allen, P. D.  Identification of a key determinant of ryanodine receptor type 1 required for activation by 4-chloro-m-cresol.  J. Biol. Chem. 278 (2003) pp. 28727-28735.

Fessenden, J. D., Chen, L., Wang, Y., Paolini, C., Franzini-Armstrong, C., Allen, P. D., and Pessah, I. N.  Ryanodine receptor point mutant E4032A reveals an allosteric interaction with ryanodine.  Proc. Natl. Acad. Sci. U.S.A. 98 (2001) pp. 2865-2870.

Wang, Y., Fraefel, C., Protasi, F., Moore, R. A., Fessenden, J. D., Pessah, I. N., DiFrancesco, A., Breakefield, X., and Allen, P. D.  HSV-1 amplicon vectors are a highly efficient gene delivery system for skeletal muscle myoblasts and myotubes.  Am. J. Physiol. Cell Physiol.  278 (2000) pp. C619-C626.

Fessenden, J. D., Wang, Y., Moore, R. A., Chen, S. R. W., Allen, P. D. and Pessah, I. N.  Divergent functional properties of ryanodine receptor types 1 and 3 expressed in a myogenic cell line.  Biophys. J. 79 (2000) pp. 2509-2525.

PubMed:
Click here for a list of publications (searches the National Library of Medicine's PubMed database.)