Fatty Acids and atrial GIRKs

I may try to understand some of this one day
but for the moment its for the pot,hope its of use . Marry Xmas, Angus

[www.jgp.org]

Cytoplasmic Unsaturated Free Fatty Acids Inhibit ATP-dependent
Gating of the G Protein–gated K+ Channel

This study reports the identification of an endogenous inhibitor of the G protein–gated (KACh) channel and its effect on the KACh
channel kinetics. In the presence of acetylcholine in the pipette, KACh channels in inside-out atrial patches were activated by
applying GTP to the cytoplasmic side of the membrane. In these patches, addition of physiological concentration of intracellular
ATP (4 mM) upregulated KACh channel activity approximately fivefold and induced long-lived openings. However, such
ATP-dependent gating is normally not observed in cell-attached patches, indicating that an endogenous substance that inhibits the
ATP effect is present in the cell. We searched for such an inhibitor in the cell. ATP-dependent gating of the KACh channel was inhibited by the addition of the
cytosolic fraction of rat atrial or brain tissues. The lipid component of the cytosolic fraction was found to contain the inhibitory activity. To identify the lipid inhibitor,
we tested the effect of ~40 different lipid molecules. Among the lipids tested, only unsaturated free fatty acids such as oleic, linoleic, and arachidonic acids (0.2–2
µM) reversibly inhibited the ATP-dependent gating of native KACh channels in atrial cells and hippocampal neurons, and of recombinant KACh channels (GIRK1/4
and GIRK1/2) expressed in oocytes. Unsaturated free fatty acids also inhibited phosphatidylinositol-4,5-bisphosphate (PIP2)-induced changes in KACh channel
kinetics but were ineffective against ATP-activated background K1 channels and PIP2-activated KATP channels. These results show that during agonist-induced
activation, unsaturated free fatty acids in the cytoplasm help to keep the cardiac and neuronal KACh channels downregulated by antagonizing their ATP-dependent
gating. The opposing effects of ATP and free fatty acids represent a novel regulatory mechanism for the G protein–gated K+ channel.

Hi Angus

I would like to understand this too. I read about G proteins and K channels a while back. I think there is something in it too.

Merry Xmas to you and all too

Fran