The KCNQ1 voltage-gated potassium (Kv) channel pore-forming (a) subunit is ubiquitously expressed and linked to life-threatening human disorders including Long QT syndrome, atrial fibrillation and diabetes. KCNQ1 exhibits a high degree of functional flexibility enabled by co-assembly with KCNE family ? subunits, facilitating roles both in excitable cell repolarization, and as a constitutively active K+ channel in polarized epithelial cells. Na+-coupled solute transport is crucial for uptake of ions and solutes including sugars and myo-inositol, an important osmolyte and precursor for cell signaling molecules. We recently discovered that KCNQ1 forms complexes with several different Na+-coupled solute transporters, and that at least two of these novel complexes are required for normal epithelial cell activity - in the thyroid and choroid plexus. Using in vitro functional studies, we found that KCNQ1 and the Na+-dependent myo-inositol transporters SMIT1 and SMIT2 reciprocally regulate each other's function. We also recently identified several other channel-transporter interactions, including KCNQ4-SMIT1, KCNQ1-SGLT1 (Na+-coupled glucose transporter), and KCNQ1-NIS (Na+/I- symporter). Here, we will elucidate molecular mechanisms of function, interaction, and physiological relevance of this novel and potentially widespread class of macromolecular signaling complexes. Three main questions are addressed. First, which channel domains and functions regulate transporter activity? Using mutagenesis, pharmacological agents and functional analyses, we will test the hypothesis that the KCNQ1 pore and voltage sensor modules can independently influence activity of co-assembled solute transporters. We will also use protein biochemistry in conjunction with channel chimeras and mutagenesis to elucidate channel domains crucial for physical interaction with transporters, in vitro. Second, why are channel-transporter complexes required? Using electrophysiological and solute uptake assays in vitro we will test the hypothesis that KCNQ1 acts as a biosensor in complexes with SMIT1 and SMIT2, facilitating responses to changes in osmolarity, membrane lipid composition, pH and Ca2+. Third, where do channel-transporter complexes occur in vivo? Aided by several knockout mouse lines, we will locate channel-transporter complexes, and utilize positron emission tomography to specifically test for the requirement of KCNQ1-KCNE regulation of SGLT family transporters, in vivo. Na+-coupled solute transporters, and Kv channel a subunits including KCNQ1, exhibit broad distribution, wide tissue expression overlap, and high biomedical significance. Together with our recent findings, this suggests that potassium channel-transporter complexes have the potential to be highly influential in mammalian physiology and in the pathogenesis of a number of prevalent human disorders.

Public Health Relevance

Voltage-gated ion channels control electrical activity in the body and are essential for processes including thought and movement, breathing and the heart-beat. Sodium-coupled solute transporters also regulate these activities and are essential for cellular uptake of vital ions and nutrients. Having recently discovered that proteins in these two classes interact, we will now uncover mechanisms for these interactions, and how they are regulated, to better understand their roles in human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115189-03
Application #
9206169
Study Section
Special Emphasis Panel (NTRCM)
Program Officer
Chin, Jean
Project Start
2015-04-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$253,890
Indirect Cost
$80,640
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Abbott, Geoffrey W (2017) Chansporter complexes in cell signaling. FEBS Lett 591:2556-2576
Manville, RĂ­an W; Neverisky, Daniel L; Abbott, Geoffrey W (2017) SMIT1 Modifies KCNQ Channel Function and Pharmacology by Physical Interaction with the Pore. Biophys J 113:613-626
Neverisky, Daniel L; Abbott, Geoffrey W (2017) KCNQ-SMIT complex formation facilitates ion channel-solute transporter cross talk. FASEB J 31:2828-2838
Abbott, Geoffrey W (2016) KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene 576:1-13
Abbott, Geoffrey W; Roepke, Torsten K (2016) KCNE2 and gastric cancer: bench to bedside. Oncotarget 7:17286-7
Abbott, Geoffrey W (2016) KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis. Gene 593:249-60
Abbott, Geoffrey W (2016) Channel-transporter complexes: an emerging theme in cell signaling. Biochem J 473:3759-3763
Abbott, Geoffrey W; Jepps, Thomas A (2016) Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity. J Vasc Res 53:138-148
Abbott, Geoffrey W (2015) The KCNE2 K? channel regulatory subunit: Ubiquitous influence, complex pathobiology. Gene 569:162-72
Neverisky, Daniel L; Abbott, Geoffrey W (2015) Ion channel-transporter interactions. Crit Rev Biochem Mol Biol 51:257-67