Inactivation of the High-Affinity Ca2+ Uptake System Delays the Amiodarone-Induced Ca2+ Influx in Yeast Ogataea parapolymorpha

The antiarrhythmic drug amiodarone is toxic to yeast cells due to provoking Ca²⁺ entry into cytosol. Here we show that in <i>Ogataea parapolymorpha</i>, the loss of Cch1 or Mid1, which are the primary components of the high-affinity Ca²⁺ uptake system (HACS), leads to a delay in the rise of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) in response to amiodarone. This has negligible effect on the ability of the strain with the unaffected Ca²⁺ sequestration system to grow in the presence of amiodarone. Inactivation of the <i>PMC1</i> gene encoding the Ca²⁺ ATPase involved in the cytosolic Ca²⁺ sequestration in the vacuole dramatically increases sensitivity to amiodarone, while inactivation of <i>CCH1</i> or <i>MID1</i> suppresses it. This correlates with a substantially lower [Ca²⁺]_cyt rise in response to amiodarone when the genes encoding the HACS components are inactivated in the mutant lacking Pmc1. Similarly to sodium dodecyl sulfate, which has also been shown to increase [Ca²⁺]_cyt, amiodarone causes activation of the Hog1 protein kinase involved in the cell cycle regulation. The role of HACS in the amiodarone-induced Ca²⁺ influx is discussed.