title: Design of versatile biochemical switches that respond to amplitude, duration, and spatial cues.
abstract: Cells often mount ultrasensitive (switch-like) responses to stimuli. The design principles underlying many switches are not known. We computationally studied the switching behavior of GTPases, and found that this first-order kinetic system can show ultrasensitivity. Analytical solutions indicate that ultrasensitive first-order reactions can yield switches that respond to signal amplitude or duration. The three-component GTPase system is analogous to the physical fermion gas. This analogy allows for an analytical understanding of the functional capabilities of first-order ultrasensitive systems. Experiments show amplitude- and time-dependent Rap GTPase switching in response to Cannabinoid-1 receptor signal. This first-order switch arises from relative reaction rates and the concentrations ratios of the activator and deactivator of Rap. First-order ultrasensitivity is applicable to many systems where threshold for transition between states is dependent on the duration, amplitude, or location of a distal signal. We conclude that the emergence of ultrasensitivity from coupled first-order reactions provides a versatile mechanism for the design of biochemical switches.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. azi.lipshtat@mssm.edu
authors.forename: Azi
authors.initials: A
authors.lastname: Lipshtat
authors.forename: Gomathi
authors.initials: G
authors.lastname: Jayaraman
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
mesh_terms: D020558:GTP Phosphohydrolases / Q000378:metabolism*; D007700:Kinetics; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D043884:Receptor, Cannabinoid, CB1; D020558:GTP Phosphohydrolases