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Regulating membrane potential is key to cellular function. For many animal cells, resting membrane potential is predominantly driven by a family of K2P (two-pore domain) potassium channels. These channels are commonly referred to as leak channels, as their presence results in the membrane being permeable to K⁺ ions. These channels, along with various pumps and exchangers, keep the cell resting membrane potential (Rp) relatively close to potassium’s equilibrium potential (E_K); however, in many cells, the resting membrane potential is more depolarized than the E_K due to a small Na⁺ ion leak. Raising [Ca²⁺]_O (extracellular Ca²⁺ concentration) can result in hyperpolarization of the membrane potential from the resting state. The mechanism for this hyperpolarization likely lies in the blockage of a Na⁺ leak channel (NALCN) and/or voltage-gated Na⁺ channels. The effects may also be connected to calcium-activated potassium channels. Using <i>Drosophila melanogaster</i>, we here illustrate that changing [Ca²⁺]_O from 0.5 to 3 mM hyperpolarizes the muscle. Replacing NaCl with LiCl or choline chloride still led to hyperpolarization when increasing [Ca²⁺]_O. Replacing CaCl₂ with BaCl₂ results in depolarization. K2P channel overexpression in the larval muscle greatly reduces the effects of [Ca²⁺]_O on cell membrane potential, likely because potential is heavily driven by the E_K in these muscles. These experiments provide an understanding of the mechanisms behind neuronal hypo-excitability during hypercalcemia, as well as the effects of altered expression of K2P channels on membrane potential.