Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca(2+) release in heart failure.

Abstract

OBJECTIVE:

Little information is available as to the Ca(2+) release function of the sarcoplasmic reticulum (SR) in heart failure. We assessed whether the alteration in this function in heart failure is related to a change in the role of FK binding protein (FKBP), which is tightly coupled with the cardiac ryanodine receptor (RyR) and recently identified as a modulatory protein acting to stabilize the gating function of RyR.

METHODS:

SR vesicles were isolated from dog LV muscles [normal (N), n=6; heart failure induced by 3-weeks pacing (HF), n=6]. The time course of the SR Ca(2+) release was continuously monitored using a stopped-flow apparatus, and [3H]ryanodine-binding and [3H]dihydro-FK506-binding assays were also performed.

RESULTS:

FK506, which specifically binds to FKBP12.6 and dissociates it from RyR, decreased the polylysine-induced enhancement of [3H]ryanodine-binding by 38% in N (P<0.05) but it had no effect in HF. In HF, the rate constant for the polylysine-induced Ca(2+) release from the SR was 61% smaller than in N. FK506 decreased the rate constant for the polylysine-induced Ca(2+) release by 67% in N (P<0.05) but had no effect in HF. The [3H]dihydro-FK506-binding assay revealed that the number (B(max)) of FKBPs was decreased by 83% in HF (P<0.05), while the K(d) value was unchanged. FK506 did not significantly change SR Ca(2+.)-ATPase activity in either N or HF.

CONCLUSIONS:

In HF, the number of FKBPs showed a tremendous decrease; this may underlie the RyR-channel instability and the impairment of the Ca(2+) release function of RyR seen in the failing heart.

• Authors: K Ono, M Yano, T Ohkusa, M Kohno, T Hisaoka, T Tanigawa, S Kobayashi, M Kohno, M Matsuzaki
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 48 Issue 2 Pg. 323-31 (Nov 2000) ISSN: 0008-6363 [Print] England
• PMID: 11054478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ryanodine Receptor Calcium Release Channel
• Ryanodine
• Polylysine
• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B
• Calcium
• Tacrolimus

Topics

• Analysis of Variance
• Animals
• Calcium (metabolism)
• Cardiac Pacing, Artificial
• Dogs
• Female
• Heart Failure (metabolism)
• Male
• Polylysine (pharmacology)
• Protein Binding (drug effects)
• Ryanodine (chemistry, metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Tacrolimus (chemistry, pharmacology)
• Tacrolimus Binding Proteins (metabolism)