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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.
Highlights
Cardiac GIRK channels play a central role in parasympathetic slowing of the heart
The critical role of parasympathetic regulation of cardiac GIRK channels is evident from the severe diseases that result from mutations in the GIRK gene such as Atrial Fibrillation (Kovoor et al, 2001; Voigt et al, 2010), and Long QT syndrome (Yang et al, 2010)
It is unclear to what extent GIRK4 homo-tetramers versus GIRK1/4 hetero-tetramers dominate in cardiac cells
Summary
Cardiac GIRK channels play a central role in parasympathetic slowing of the heart. Activated M2Rs release inhibitory G protein alpha subunits and Gbg. Gbg is a hetero-dimeric protein composed of tightly bound beta and gamma subunits. Gbg is a hetero-dimeric protein composed of tightly bound beta and gamma subunits This free Gbg, along with its lipid anchor, diffuses on the intracellular membrane surface and binds directly to GIRK to activate it (Logothetis et al, 1987; Whorton and MacKinnon, 2013; Sakmann et al, 1983; Kurachi et al, 1986). Activation of GIRK shifts the resting membrane potential of pacemaker cells toward the equilibrium potential for K+, lengthening the interval between cardiac action potentials and thereby slowing the heart (Loewi and Navratil, 1926; Rayner and Weatherall M, 1959). The critical role of parasympathetic regulation of cardiac GIRK channels is evident from the severe diseases that result from mutations in the GIRK gene such as Atrial Fibrillation (Kovoor et al, 2001; Voigt et al, 2010), and Long QT syndrome (Yang et al, 2010)
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