Sodium Channel Modulation

Sarhan, M.F., Van Petegem, F. and Ahern, C.A. "A conserved double tyrosine motif in the cardiac sodium channel domain III-IV linker underlies calcium/calmodulin binding and inactivation gating." Sept, 2009, In Press at J. Biol. Chem. [PubMed]

Ahern, C.A., Zhang, J.F., Woolkalis, M.J., and Horn, R. "Modulation of the Cardiac Sodium Channel NaV1.5 by the Src Family Tyrosine Kinase Fyn." Circulation Research 2005 96: 991 – 998 [PubMed]

Excitation-contraction coupling

Ahern, C. A, Arikkath, J., Vallejo, P., Gurnett, C., Powers, P., Campbell, K.P., and Coronado, R. "Intramembrane charge movements and excitation-contraction coupling expressed by two-domain fragments of the Ca2+ channel." 2001 Proc Natl Acad Sci USA, 98 (12) 6935-6940 [PubMed]

Ahern, C. A., Sheridan, D.C., Cheng, W., Mortenson, L., Allen, P.D. and Coronado, R. "Ca2+ current and charge movements in skeletal myotubes promoted by the β subunit of the dihydropyridine receptor in the absence of ryanodine receptor type 1." 2003, Biophys J. 84, 942-59 [PubMed]

Ahern, C. A., Bhattacharya,D., Mortenson, L. and Coronado, R. "A component of excitation-contraction coupling in the absence of the T671-L690 and L720-Q765 regions of the II-III loop of the dihydropyridine receptor α1s pore subunit." 2001 Biophys. J. 81, 3294-3307 [PubMed]

Voltage-sensing mechanisms

Ahern, C.A. and Horn, R. "Focused electric field across the voltage sensor of a Potassium channel." Neuron, 2005: 48 (1), 25-29 [PubMed]

Ahern, C.A. and Horn, R. "Specificity of charge-carrying residues in the voltage sensor of potassium channels." J Gen Physiol. 2004 Mar;123(3):205-16 [PubMed]

Ahern, C.A. and Horn, R. "Stirring up controversy with a voltage sensor paddle." TRENDS in Neurosciences 2004, Vol 27, No. 6: 303-307 [PubMed]

Unnatural amino acid mutagenesis

Ahern, C.A and Kobertz W. "Chemical Tools Used to Tinker with Voltage-gated Ion Channels". Biochemistry, 2009, 48(3):517-260 [PubMed]

Ahern, C.A, Eastwood, A.L., Dougherty, D.A. and Horn, R. "Role of Electrostatics in the Slow Inactivation of Shaker Potassium Channels." J Gen. Physiol. 2009 Dec;134(6):461-9 [PubMed] [Commentary]

Ahern, C.A, Eastwood, A.L., Dougherty, D.A. and Horn, R. "Electrostatic contributions of aromatic residues in the local anesthetic receptor in voltage-gated sodium channels." 2008, Circulation research, 102: 86-94 [PubMed]

Santarelli, V.P., Eastwood, A.L., Dougherty, D.A., Horn, R. and Ahern, C.A. "A cation-pi interaction with tyrosine 401 is the basis for tetrodotoxin sensitivity in the voltage-gated sodium channel NaV1.4." J. Biol. Chem. 2007, 282: 8044-8051 [PubMed]

Ahern, C.A, Eastwood, A.L., Lester, H.A., Dougherty, D.A. and Horn, R. "A cation:pi interaction between extracellular TEA and an aromatic residue in potassium channels." J. Gen. Physiol. 2006;128(6):649-657 [PubMed]

Research interests

The Ahern laboratory at the University of British Columbia is interested in voltage-gated sodium channels as regulators of excitability in nervous and muscle tissue. Our efforts are currently focused on two general topics. First, sodium channels control the upstroke of the action potential in excitable cells making them valuable therapeutic targets in the management of cardiac arrhythmias, epilepsy and pain. We are therefore interested in how sodium-channel inhibitors known as local anesthetics, anti-arrhythmics, and anti-convulsants interact with amino acid side-chains in the channels drug receptor. Our current studies use a combination of site-directed unnatural amino acid mutagenesis and ab initio quantum mechanical calculations to better understand the electrostatic relationships between these cationic drugs and conserved aromatic residues in the channel’s inner vestibule. We also aim to better understand how sodium channels ‘gate’, that is, open, close and inactivate in response to changes in trans-membrane potential. We will enlist a variety of traditional and cutting-edge molecular biological tools for this purpose.