title: The GIRK1 subunit potentiates G protein activation of cardiac GIRK1/4 hetero-tetramers.
abstract: G protein gated inward rectifier potassium (GIRK) channels are gated by direct binding of G protein beta-gamma subunits (Gβγ), signaling lipids, and intracellular Na(+). In cardiac pacemaker cells, hetero-tetramer GIRK1/4 channels and homo-tetramer GIRK4 channels play a central role in parasympathetic slowing of heart rate. It is known that the Na(+) binding site of the GIRK1 subunit is defective, but the functional difference between GIRK1/4 hetero-tetramers and GIRK4 homo-tetramers remains unclear. Here, using purified proteins and the lipid bilayer system, we characterize Gβγ and Na(+) regulation of GIRK1/4 hetero-tetramers and GIRK4 homo-tetramers. We find in GIRK4 homo-tetramers that Na(+) binding increases Gβγ affinity and thereby increases the GIRK4 responsiveness to G protein stimulation. GIRK1/4 hetero-tetramers are not activated by Na(+), but rather are in a permanent state of high responsiveness to Gβγ, suggesting that the GIRK1 subunit functions like a GIRK4 subunit with Na(+) permanently bound.
authors.affiliation: Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States.
authors.forename: Kouki K
authors.initials: KK
authors.lastname: Touhara
authors.affiliation: Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States.
authors.forename: Roderick
authors.identifier: 0000-0001-7605-4679
authors.initials: R
authors.lastname: MacKinnon
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009829:Oleic Acids / Q000737:chemistry / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011510:Proteolipids / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D014162:Transfection
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C484274:KCNJ5 protein, human; D009829:Oleic Acids; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D021122:Protein Subunits; D011510:Proteolipids; D011994:Recombinant Proteins; C020485:proteoliposomes; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; D012964:Sodium
keywords: G protein; G protein gated potassium channel; biochemistry; biophysics; cardiac physiology; hetero-tetrameric ion channel; human; mouse; planar lipid bilayer; sodium activation; structural biology