Key result
PKC activation attenuates K+ currents ~19% in control but not hypothyroid or diabetic rat myocytes.
Why the study?
The regulation of cardiac K+ currents by protein kinase C and its modification by hormonal status in hypothyroid and diabetic conditions were unclear.
p-value: p=< 0.001
PKC-mediated suppression of cardiac K+ currents is mediated by PKCepsilon translocation, which is altered under hypothyroid and diabetic conditions due to chronic translocation.
Altered PKCε translocation may blunt K+ current regulation in hypothyroid and diabetic rat myocytes; leaves open its role in human arrhythmogenesis.
The effects of protein kinase C (PKC) activation on cardiac K+ currents were studied in rat ventricular myocytes, using whole-cell voltage clamp methods. Control rats were compared to hypothyroid or diabetic rats, in which PKC expression and activity were enhanced. 2. In control myocytes, two calcium-independent outward K+ currents, the transient It and the sustained Iss, were attenuated by 18.9 +/- 2.0 and 16.8 +/- 3.5 %, respectively (mean +/- s.e.m.), following addition of a synthetic analogue of diacylglycerol, DiC8 (20 microM). In myocytes from hypothyroid or diabetic rats, It and Iss were not affected by DiC8. 3. The effects of DiC8 were restored in myocytes from thyroidectomized rats by injection of physiological doses of tri-iodothyronine (T3; 10 microg kg-1 for 6-8 days). Incubating cells from diabetic rats with 100 nM insulin for 5-9 h also restored the ability of DiC8 to attenuate It and Iss. 4. The attenuation of K+ currents by DiC8 in control cells was absent in the presence of a peptide known to inhibit the translocation of the isoform PKCepsilon (EAVSKPLT, 24 microM introduced through the recording pipette). A scrambled peptide (LSETKPAV) was without effect. 5. Under hypothyroid conditions the inhibitory peptide restored the effects of DiC8 on It and Iss. These currents were attenuated by 11.9 +/- 1. 5 and 9.8 +/- 1.5 %, respectively, which was significantly (P < 0. 001) more than without the peptide or with the scrambled peptide. 6. These results show that the PKC-mediated suppression of cardiac K+ currents is normally mediated by PKCepsilon translocation. This effect is absent under hypothyroid and diabetic conditions, presumably due to prior PKC activation and translocation. A PKCepsilon translocation inhibitor restores the ability of DiC8 to attenuate K+ currents under hypothyroid conditions. This presumably reflects a (partial) reversal of a chronic translocation and a shift in the balance between PKC and its anchoring proteins.
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Y. Shimoni (1999) studied Hypothyroidism and diabetes. DiC8 (synthetic analogue of diacylglycerol) vs. Hypothyroid or diabetic rat myocytes was evaluated on Attenuation of transient (It) and sustained (Iss) outward K+ currents (p=< 0.001). PKC activation by DiC8 attenuated K+ currents by 18.9% in control rat myocytes but not in hypothyroid or diabetic rats, an effect restored by a PKCepsilon translocation inhibitor (P<0.001).
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