Insight: Research Edition

Fall 2005

Understanding Protein Structures May Help Improve Pain Medications

Whether working on patients in a clinical setting, working on elephants in the wilds of Cameroon, or working on calcium channels in his laboratory at Colorado State University, Dr. William Horne’s overarching mission is to alleviate pain and suffering.

Dr. Horne, an Associate Professor in the Department of Biomedical Sciences, is a member of the Program in Molecular, Cellular and Integrative Neurosciences, and is Co-Director of the Center for Comparative Pain Medicine. His basic research into voltage-gated calcium channels and the protein complexes of which they are comprised is a far cry from the operating rooms where he has worked as an anesthesiologist helping patients through surgeries and administering post-operative pain relief. But the two are intertwined as Dr. Horne is able to see in a clinical setting where his laboratory research may one day lead – to improved analgesics that shut down pain more effectively and with fewer side effects.

“Our laboratory is looking at calcium channel structures, in particular the structure of a subunit referred to as beta 4 which seems to have dramatic effects on the gating kinetics (opening and closing) of the calcium channel,” said Dr. Horne. “These voltage-gated calcium channels coordinate a variety of calcium-dependent processes in excitable cells (such as nerve and cardiac cells) including gene expression, signal propagation and neurotransmitter release.”

Neurotransmitters enable the transmission of pain so blocking the release of neurotransmitters inhibits pain. Before researchers can look to improve pain treatment by regulating the actions of calcium channels, they have to understand the molecular structure of these channels and the protein-protein interactions that occur between channel proteins and signaling molecules. The target protein Dr. Horne’s laboratory studies is modular and typically has three subunits – alpha 1, alpha 2/delta and beta. All three subunits have been shown to play a major role in regulating pain transmission. His current work focuses on the alpha 2/delta and beta subunits.

“We want to understand what these protein subunits do when they combine with alpha 1 (the pore-forming subunit) to form a channel complex,” said Dr. Horne. “Our research shows that the beta 4 subunit definitely affects gating kinetics and may have a critical role as director of channel modulation by somehow coordinating all molecular and electrical signaling events. Defining the structure of this important subunit will answer some critical questions as to its role in calcium channel function and pain.”

Once researchers understand how the alpha and beta subunits interact, it may be possible to use this information to help create the next generation of pain relieving drugs.

Dr. Horne, who is board certified in veterinary anesthesiology, first became interested in calcium channels when he was a resident at Cornell University.

“I became fascinated with the target protein,” said Dr. Horne. “When I started my PhD, I worked on the actual structure of the protein complex. At the time I was publishing several papers focused on the global structure of these proteins, powerful techniques in molecular biology exploded onto the research scene. I went on to Stanford to do a post-doc and became heavily involved with cloning multiple types of calcium channels from the brain and spinal cord.”

The collective efforts of many researchers led to the discovery of 10 genes that code for calcium channel alpha 1 subunits: Dr. Horne was the first to discover one of them. After finishing his post-doc, Dr. Horne went to work for Neurex Corp. where he worked with a team that studied the use of a marine snail toxin as an analgesic agent. The toxin acts as a calcium channel blocker to prevent transmission of pain. The company eventually developed the toxin into a drug that was just recently approved by the Federal Drug Administration. Dr. Horne said he enjoyed working at Neurex but came to miss veterinary medicine. He took a position at North Carolina State and then joined the faculty at Colorado State in 2003. In addition to his laboratory and clinical work, Dr. Horne is involved as a veterinary anesthesiologist in a program in Cameroon to equip elephants with satellite tracking collars to aid in population studies and herd control.