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Cytochalasin D reduces Ca²⁺ sensitivity and maximum tension via interactions with myofilaments in skinned rat cardiac myocytes

S. C. Calaghan, E. White, S. Bedut and J.-Y. Le Guennec

1. The F-actin disrupter cytochalasin D depresses cardiac contractility, an effect previously ascribed to the interaction of cytochalasin D with cytoskeletal actin. We have investigated the possibility that this negative inotropic effect is due to the interaction of cytochalasin D with sarcomeric actin of the thin filament.

2. Confocal images of Triton X-100-skinned myocytes incubated with a fluorescent conjugate of cytochalasin D revealed a longitudinally striated pattern of binding, consistent with a myofibrillar rather than cytoskeletal structure.

3. Tension-pCa relationships were determined at sarcomere lengths (SLs) of 2.0 and 2.3 m following 2 min incubation with 1 M cytochalasin D. Cytochalasin D significantly reduced the pCa for half-maximal activation (pCa₅₀) at both SLs. The shift in pCa₅₀ was significantly greater at a SL of 2.3 m compared with that at a SL of 2.0 m. Cytochalasin D had no effect on the Hill co-efficient at either SL.

4. Cytochalasin D significantly reduced the maximum tension at both SLs.

5. We suggest that the length-dependent decrease in myofilament Ca²⁺ sensitivity in response to cytochalasin D is due to a decrease in the affinity of troponin C for Ca²⁺.

6. Cytochalasin D has been used for many years as the agent of choice for disruption of cytoskeletal actin. However, we have demonstrated for the first time an interaction of cytochalasin D with sarcomeric actin of the thin filament, which can account for the effects of cytochalasin D on cardiac contractility.

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