Depolarization of the plasma membrane during neurotransmitter release or muscle excitation/contraction involves increases in intracellular Ca2+. Homeostasis is reestablished through the action of various enzymes, including ion pumps. PMCAs (Plasma Membrane Calcium ATPases) belong to the P-type family of transport ATPases which couple ATP hydrolysis to the export of intracellular Ca2+. They are characterized by large molecular mass, high affinity for Ca2+, and direct regulation by interaction with Ca2+/calmodulin. Four different genes (PMCA 1-4) and independent alternative splice sites combine to generate multiple PMCA isoforms. PMCA 1-4 are highly homologous, but differ substantially in their N-terminal regions. PMCA1 and 4 are ubiquitously expressed and perform housekeeping roles. However, PMCA2 and 3 exhibit tissue-specific expression and perform more specialized functions. Although PMCA2 and 3 are both expressed to some degree in muscle, PMCA2 is primarily found in the cerebellum. There, it accounts for the majority of neural pump protein. Thus, PMCA2 is thought to be the principal ATPase that functions to maintain Ca2+ homeostasis in response to neural excitation.