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Calpeptin, Not Calpain, Directly Inhibits an Ion Channel of the Inner Mitochondrial Membrane

Calpeptin, Not Calpain, Directly Inhibits an Ion Channel of the Inner Mitochondrial Membrane

Maria Derksen, Christian Vorwerk, Detlef Siemen

Protoplasma. 2016 May;253(3):835-843.

PMID: 26108743

Abstract:

The permeability transition pore (PTP) of inner mitochondrial membranes is a large conductance pathway for ions up to 1500 Da which opening is responsible for ion equilibration and loss of membrane potential in apoptosis and thus in several neurodegenerative diseases. The PTP can be regulated by the Ca(2+)-activated mitochondrial K channel (BK). Calpains are Ca(2+)-activated cystein proteases; calpeptin is an inhibitor of calpains. We wondered whether calpain or calpeptin can modulate activity of PTP or BK. Patch clamp experiments were performed on mitoplasts of rat liver (PTP) and of an astrocytoma cell line (BK). Channel-independent open probability (P(o)) was determined (PTP) and, taking into account the number of open levels, NP(o) by single channel analysis (BK). We find that PTP in the presence of Ca(2+) (200 μM) is uninfluenced by calpain (13 nM) and shows insignificant decrease by the calpain inhibitor calpeptin (1 μM). The NP(o) of the BK is insensitive to calpain (54 nM), too. However, it is significantly and reversibly inhibited by the calpain inhibitor calpeptin (IC50 = 42 μM). The results agree with calpeptin-induced activation of the PTP via inhibition of the BK. Screening experiments with respirometry show calpeptin effects, fitting to inhibition of the BK by calpeptin, and strong inhibition of state 3 respiration.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP117591205-A	Calpeptin		117591-20-5	Price

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