Nazzareno D'Avanzo

Research

Inward rectifier K+ channels (variously classified as “Kir”, “IRK” or “KCNJ” proteins) play numerous key physiological roles, particularly in stabilizing the resting membrane potential, and regulating K+ ion flux across cellular membranes. These channels are expressed in a wide variety of cells including skeletal, cardiac, and vascular myocytes, neurons, and pancreatic -cells. Mutations in KCNJ channels, or defects in their regulation, have been linked to a wide variety of disorders, including Bartter’s Syndrome (KCNJ1), epilepsy (KCNJ10), the rare genetic cardiac disorders Andersen-Tawil Syndrome (KCNJ2) and Smith-Magenis Syndrome (KCNJ12), and Type II Diabetes (KCNJ11). Thus, the KCNJ channel family presents an attractive target for the development of novel therapeutic agents for numerous diseases.

Recent x-ray crystallographic structures of bacterial inward rectifier K+ channel (PDB entries: 1P7B, 1XL4, 1XL6, 2QKS) have contributed significantly to our understanding of the structure and function of this important family of ion channels. However, with less than 30% sequence identity, contrary regulation by PIP(4,5)2 and different residues in regions known to be critical for eukaryotic KCNJ channel function, important questions still remain: do the structures of KirBac1.1 and KirBac3.1 channels reflect those of eukaryotic inward rectifier channels? What is the molecular basis for differences in bacterial and eukaryotic inward rectifier channel regulation? Furthermore, what is the molecular basis for functional differences between the various eukaryotic inward rectifier channel isoforms? And what movements are involved during the gating process (opening and closing of the channel)?

Using a combination of biophysical and crystallographic approaches, I aim to carefully examine these questions.