Faculty Research Page
Assistant Professor of NeurobiologyLab Homepage: http://www.brohawnlab.org/
Sensation of environmental stimuli, thought, learning, memory, and other aspects of neuronal communication, hormone secretion and movement all rely on cellular electrical signals. We study life’s electrical system from a molecular and biophysical perspective. The focus of the laboratory is on ion channels, transporters and their regulatory complexes that form gated pathways for ionic traffic across cell membranes. We aim to discover how these membrane proteins work at a detailed mechanistic level and what they do in a biological context. To this end, we utilize a range of approaches including structural biology (X-ray crystallography and cryo-EM), electrophysiology, biophysics, biochemistry, pharmacology and imaging. Our goals are to understand the molecular basis of sensory transduction and electrical signaling and to lay the groundwork for development of new approaches to promoting health and treating disease.
Currently, the major interest of the lab is force sensation in biology. Simply put - how do we feel? Remarkably, in many ways we still do not know the answer this question. The transduction of physical forces into cellular signals, or mechanosensation, underlies such basic processes as touch, hearing, proprioception and pain sensation, osmotic force regulation, blood pressure control, and cell growth and development. Dysregulation of mechanosensation is associated with disease and pathophysiology including deafness, atherosclerosis, chronic pain and cancer. In some cases, ion channels are directly responsible for converting mechanical forces into cellular electrical signals, but identification of these channels is ongoing and many important questions remain unanswered. In other cases, the molecular machinery involved in force transduction may be more complex. A diverse set of proteins have been implicated in force sensation including ion channels from the Piezo, K2P, TRP, Deg/ENaC, VGIC, TMC, SWELL, OSCA, MscS and MscL families. How exactly are these channels involved in force sensation? What is the mechanistic basis of their mechanosensitivity? How are they regulated by other factors including interacting partners, small molecules, lipids or temperature? We address these questions with parallel structural and functional approaches. Structures of channels in distinct conformational states are solved using X-ray crystallography or cryo-EM to provide insight into their architecture and principles of ion conduction and gating. Functional studies in reconstituted systems and in cells using electrophysiological, biochemical and biophysical techniques are performed to probe mechanistic hypotheses and delineate how force is ultimately coupled to channel gating.
A current limitation in the study of force sensation is a lack of specific tools (e.g. pharmacological, immunological and imaging reagents) that can be used to ask targeted questions about the molecules involved in a given biological process. For instance, where are various force sensors expressed in animals at tissue, cellular and subcellular levels? How is a given cell’s response to stimulus shaped by the collection of sensors it expresses? Could manipulation of specific sensors have potential clinical implications? We are leveraging our increasingly deep mechanistic understanding of the underlying molecular machinery to develop new tools and approaches to address these questions and to better understand force sensation and other aspects of sensory transduction and electrical signaling in different physiological contexts.
Brohawn, SG, Campbell, EB & MacKinnon, R. Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature (2014) 516, 126-30. http://www.ncbi.nlm.nih.gov/pubmed/25471887
Brohawn, SG, Su, Z & MacKinnon, R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. PNAS (2014) 111, 3614–3619. http://www.ncbi.nlm.nih.gov/pubmed/24550493
Brohawn, SG, Campbell, EB & MacKinnon, R. Domain-swapped chain connectivity and gated membrane access in a Fab-mediated crystal of the human TRAAK K+ channel. PNAS (2013) 110, 2129–2134. http://www.ncbi.nlm.nih.gov/pubmed/23341632
Brohawn, SG, del Mármol, J & MacKinnon, R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science (2012) 335, 436–441. http://www.ncbi.nlm.nih.gov/pubmed/22282805
Brohawn, SG & Schwartz, TU. Molecular architecture of the Nup84-Nup145C-Sec13 edge element in the nuclear pore complex lattice. Nature Structure and Molecular Biology (2009) 16, 1173–1177. http://www.ncbi.nlm.nih.gov/pubmed/19855394
Brohawn, SG, Leksa, NC, Spear, ED, Rajashankar, K & Schwartz, TU. Structural evidence for common ancestry of the nuclear pore complex and vesicle coats. Science (2008) 322, 1369–1373. http://www.ncbi.nlm.nih.gov/pubmed/18974315
Photo Credit: Mark Hanson of Mark Joseph Studios
Last Updated 2015-08-25