Nobel Laureate Roderick MacKinnon Describes How Ion Channels Work
Wednesday Afternoon Lecture Series Presentation in September 2017
BY ANNE DAVIDSON, NICHD
Listening to Nobel Laureate Roderick MacKinnon describe how ion channels function is like having Microsoft co-founder Bill Gates explain binary code. MacKinnon was the opening act for the 2017-2018 season of the NIH Director’s Wednesday Afternoon Lecture Series (WALS), held on September 27, 2017, in Masur Auditorium (Building 10).
CREDIT: DALE LEWIS, NCI
Nobel laureate Roderick MacKinnon presented a WALS lecture on the biophysics and biology of potassium ion channels.
MacKinnon, currently a John D. Rockefeller Jr. Professor and Howard Hughes Medical Investigator at The Rockefeller University (New York), received the 1999 Albert Lasker Basic Medical Research Award (shared with Clay Armstrong and Bertil Hille) for “his elucidation of the structure and function of potassium channels [providing] the first molecular description of an ion selective channel” and the 2003 Nobel Prize in chemistry (shared with Peter Agre) “for structural and mechanistic studies of ion channels.”
“The love of his life [is] how ion channels work,” said Anirban Banerjee during his introduction of MacKinnon at the lecture. Banerjee was MacKinnon’s postdoc at The Rockefeller University in New York (2006–2012) and is now a principal investigator in the National Institute of Child Health and Human Development.
Ion channels are pivotal in many biological processes, such as controlling the pace of the heart, regulating the secretion of hormones, and generating electrical impulses in the nervous system. Dysfunctions in the channels are linked to physiological, neuronal, and other disorders.
Banerjee recalled lively lab meetings at Rockefeller among MacKinnon’s graduate students and postdocs. MacKinnon would listen patiently and then would break in with a remarkably insightful soliloquy. Such insights were pivotal when Banerjee and MacKinnon successfully used a pore-blocking toxin to show the first co-crystal structure of a potassium channel.
But MacKinnon’s path to Rockefeller was not an easy one. He wanted to be able to visualize his love—the potassium ion channel; however, when he started working on channel proteins at Harvard Medical School (Boston), the structure had not been solved. The pervading view in the field at the time (1990s) and among MacKinnon’s own colleagues was that a structure of ion channels was impossible to determine because 1) they are membrane proteins only a few, naturally abundant membrane proteins had been characterized at that time; and 2) they exist in a mixture of states.
So despite a lack of faith among his colleagues, MacKinnon left Harvard for Rockefeller, where he set up a lab that used X-ray crystallography to determine the structures of ion channels. The move was a challenge: MacKinnon, who was was trained in electrophysiology, had to transition to structural biology and learn crystallography. “Rod was just stubborn and so driven by the question,” Banerjee explained.
The question driving MacKinnon’s early research was how the membrane channels select for potassium ions over other ions. Using monoclonal antibodies for getting crystals that would offer a higher resolution picture, he discovered the structure of the selectivity filter.
There are some 80 potassium channels in humans. Different channels have evolved to sense different environmental stimuli: chemical, mechanical, and electrical, MacKinnon said. The channels are diverse, but “what makes them a common family is that they all have…the selectivity filter.”
One channel MacKinnon discussed in the WALS lecture was the G protein-coupled inwardly rectifying potassium (GIRK) channel, which suppresses electrical activity and is activated by the G protein. G proteins (guanine nucleotide-binding proteins) act as molecular switches and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. MacKinnon’s lab did GIRK reconstitution in a synthetic lipid membrane and found that four highly cooperative beta-gamma subunits are needed to open the channel.
Recently, MacKinnon has begun delving into single-particle cryoelectron microscopy. This technique has allowed his lab to visualize the protein Slo2, a sodium-dependent potassium channel, which is activated under different sodium concentrations.
To watch a videocast of MacKinnon’s WALS talk, “Biophysics and Biology of K+ Channels,” held on September 27, 2017, go to https://videocast.nih.gov/launch.asp?23487. To see the full WALS season, go to https://oir.nih.gov/wals/current-lecture-season.