Chemical Activators of Protein Phosphatase-1 Induce Calcium Release inside Intact Cells

• PP1-disrupting peptides do not directly act on PP2A and PP2B
• PDPs can activate PP1 in a reversible or permanent manner
• PDPs can be applied to study acute and long-term effects of PP1 activation
• Chemically induced PP1 activation triggers calcium release from internal stores

SummaryProtein phosphatase-1 (PP1) is a major Ser/Thr phosphatase that is involved in numerous cellular processes. PP1-disrupting peptides (PDPs) are selective chemical tools used to study PP1. They generate catalytically active PP1 inside cells but do not bind to the closely related PP2A. Here, we show that PDPs also do not act directly on PP2B, thus demonstrating the selectivity of PDPs toward PP1. We present PDPs with different properties, enabling reversible versus permanent activation of PP1. We also show that Ca2+ spiking is an acute effect caused by PDP-induced activation of PP1. The Ca2+ is released from internal stores. Our data show that PDPs can be used as selective chemical genetics tools to study acute and long-term effects of PP1 activation in intact cells, and PDPs will therefore be valuable tools to study PP1 biology.