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Principal Investigator: DANIEL L MINOR
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $764,340
Funding agency: National Institute of Mental Health
Project Summary
The long-term goals of this project are to develop an understanding of the fundamental mechanisms that control
the function of K2P potassium channels and to identify, develop, and characterize small molecule, ion channel
modulators for the K2P family. K2Ps are a diverse family of potassium-selective channels that are responsible for
background ‘leak’ currents. These currents are pivotal in modulating the excitability of neurons. K2Ps respond to
varied stimuli that include pH changes, temperature, and mechanical force. Although K2Ps have well-established
roles in the nervous and cardiovascular systems and are implicated in pain, anesthetic responses,
thermosensation, and mood, they remain the least well-understood potassium channel class. Ion channels are
coveted drug targets. As membrane proteins, they are readily accessible to extracellular compounds and their
modulation brings about rapid changes in the properties of excitable cells in the heart and brain. However, as
membrane proteins, they also reside beyond many well-established approaches for modulator development.
Consequently, many channels, including those in the K2P family, lack significant pharmacologies. This problem
leads to a gap in our ability to connect ion channel genes with in vivo function. We are pursuing a
multidisciplinary approach that includes biophysical, structural, computational, and electrophysiological
measurements and chemical biology approaches to identify, dissect, and characterize the core elements that
control K2P function and to define and characterize new small molecules that can control K2P activity. Defining
the molecular mechanisms that control K2p activity and uncovering new K2P modulators should provide the key
framework and necessary tools for understanding how K2Ps function. Because of their important roles in human
physiology, K2Ps are targets for drugs for the treatment of chronic pain, stroke, and depression. Thus, developing
an understanding of how K2Ps function and small molecules that affect channel function should not only provide
powerful tools for dissecting K2P mechanism but should aid in the development of new therapeutic agents for a
range of human diseases.
Terms: <AD4BP protein><Ad4-binding protein><Address><Affect><Affective Disorders><Amines><Anesthestic Drugs><Anesthetic Agents><Anesthetic Drugs><Anesthetics><Apoplexy><Arrhythmia><Behavior><Binding><Binding Sites><Biochemical><Biological><Biology><Biophysics><Brain><Brain Nervous System><Brain Vascular Accident><Cardiac Arrhythmia><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemicals><Combining Site><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Development><Disulfides><Drug Targeting><Drug usage><Electron Cryomicroscopy><Electrophysiology><Electrophysiology (science)><Elements><Encephalon><Engineering><Environment><Epilepsy><Epileptic Seizures><Epileptics><FTZF1 protein><Family><Family member><Foundations><Fushi tarazu factor homolog 1><Genes><Genetic><Genetics-Mutagenesis><Goals><Heart><Heart Arrhythmias><Heart Vascular><Human><Hypertension><Intracellular Communication and Signaling><Investigation><Ion Channel><Ionic Channels><Ions><K channel><K element><K+ element><Knowledge><Lipid Binding><Lipids><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Mechanics><Membrane><Membrane Channels><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mental Depression><Modality><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Interaction><Molecular Stereochemistry><Mood Disorders><Moods><Mutagenesis><Mutagenesis Molecular Biology><NR5A1 protein><Nature><Nervous System><Neurologic Body System><Neurologic Organ System><Neurophysiology / Electrophysiology><Pain><Painful><Pharmacology><Physiology><Play><Potassium><Potassium Channel><Potassium Ion Channels><Process><Property><Protein Engineering><Reactive Site><Reagent><Role><Ru element><Ruthenium><SF 1><SF-1 transcription factor><SF1><Seizure Disorder><Signal Transduction><Signal Transduction Systems><Signaling><Single Crystal Diffraction><Site><Stimulus><Stroke><Structure><Surface Proteins><Temperature><Testing><Therapeutic Agents><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Work><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><adrenal 4 binding protein><amine><biologic><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><brain attack><cardiovascular disorder><cerebral vascular accident><cerebrovascular accident><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><circulatory system><computational studies><computer studies><conformation><conformational><conformational state><conformationally><conformations><cryo-EM><cryoEM><cryogenic electron microscopy><depression><design><designing><developmental><dimer><drug use><efficacious therapy><efficacious treatment><electrophysiological><empowerment><epilepsia><epileptogenic><extracellular><genetic approach><genetic protein engineering><genetic strategy><high blood pressure><human disease><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><in vivo><insight><interdisciplinary approach><invention><lipid bound><mechanic><mechanical><mechanical force><member><membrane structure><molecular dynamics><multidisciplinary approach><mutant><nano-molar><nanodisk><nanomolar><neuronal excitability><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear receptor 5A1 protein><particle><potassium ion><preference><pressure><protein design><response><sensory system><simulation><small molecule><social role><steroid hormone receptor Ad4BP><steroidogenic factor 1><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tool><transcription factor sf1><treat chronic pain>