Kathleen M. Giangiacomo, PhD
Associate Professor, Biochemistry
Department of Biochemistry
Potassium channels are integral membrane proteins that regulate numerous cellular processes such as muscle contraction, nerve transmission, hormone release and cell growth. The essence of potassium channel function in all of these processes relies on regulation or gating of transmembrane K+ flux through the channel pore. Our research focuses on probing the structure and function of two classes of voltage-gated potassium channels, the maxi-K and KV1 channels with peptide neurotoxins (alpha-KTx).
With their rigid, known 3D structure, and their exquisite selectivity for different potassium channels, alpha-KTx peptides are valuable molecular probes for identifying unique structural and functional features of the outer potassium channel pore. By exploring the molecular basis for alpha-KTx specificity, we have already identified novel structural features in the maxi-K and KV1.3 outer vestibules in collaboration with Dr. Ying-Duo Gao (Merck). alpha-KTx peptide affinities depend on the channel gating conformation. Consequently, mechanistic studies with these peptides may also reveal structural changes that couple channel gating and permeation.
The alpha-KTx peptides, IbTX and ChTX, display remarkable differences in their ability to discriminate between maxi-K channel complexes composed only of pore forming (alpha) subunits and those composed of alpha and auxiliary beta subunits. These associated beta subunits regulate maxi-K channel gating. With these alpha-KTx peptides as a tool, we are exploring the structural and functional relationships of alpha and beta1 subunits. In collaboration with Dr. Maria Garcia (Merck) we have identified beta1 subunit residues that modify ChTX block of single maxi-K channels and we revealed that beta1 subunits are associated with maxi-K channels in smooth but not skeletal muscle.
Maxi-K channels are important regulators of arterial tone. In a new research avenue, we are collaborating with Dr. Deborah Crabbe (Temple Cardiology Department), to explore the effects of chronic estrogen loss on maxi-K channel activity and expression in arterial smooth muscle.