Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes. Contributes to cellular Ca(2+) homeostasis in excitable cells, both in muscle and in brain (PubMed:14722618, PubMed:21593315). In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A3 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline (PubMed:14722618, PubMed:21593315). Contributes to Ca(2+) transport during excitation-contraction coupling in muscle (PubMed:14722618). In neurons, contributes to the rapid decrease of cytoplasmic Ca(2+) levels back to baseline after neuronal activation, and thereby contributes to modulate synaptic plasticity, learning and memory (PubMed:21593315). Required for normal oligodendrocyte differentiation and for normal myelination (PubMed:21959935). Mediates Ca(2+) efflux from mitochondria and contributes to mitochondrial Ca(2+) ion homeostasis (PubMed:24616101). Isoform 1 displays higher calcium exchanger activity than isoform 2, probably because isoform 1 has a lower threshold for activation by cytoplasmic Ca(2+) (PubMed:24616101). Ca(2+)(in) + 3 Na(+)(out) = Ca(2+)(out) + 3 Na(+)(in) Calcium transport is stimulated by cytoplasmic Ca(2+) and is inhibited by Na(+). Isoform 1 is more sensitive to stimulation by Ca(2+) than isoform 2. Isoform 2 is more sensitive to inactivation by Na(+). Interacts with AKAP1. Detected at neuromuscular junctions. Detected in gray and white matter in the spinal cord (PubMed:21959935). Detected in hippocampus neurons (PubMed:21593315). Detected in brain cortex neurons (PubMed:24101730). Detected in skeletal muscle (at protein level) (PubMed:14722618). Isoform 1 and isoform 2 are highly expressed in brain; levels are higher for isoform 2 (PubMed:24616101). Isoform 1 and isoform 2 are detected in soleus muscle; levels are higher for isoform 1 (PubMed:24616101). Detected in gastrocnemius muscle (PubMed:14722618). Down-regulated by hypoxia combined with glucose deprivation (at protein level). The cytoplasmic Calx-beta domains bind the regulatory Ca(2+). The first Calx-beta domain can bind up to four Ca(2+) ions. The second domain can bind another two Ca(2+) ions that are essential for calcium-regulated ion exchange. Mice appear grossly normal, are viable and fertile, but display muscle fiber necrosis; this affects less than 10% of all fibers. Muscle fibers from flexor digitorum brevis show lack of calcium exchange activity, and very slow return of cytoplasmic Ca(2+) to baseline levels after stimulation with caffeine, a stimulus that triggers release of Ca(2+) stores from the sarcoplasmic reticulum. Mutant mice display decreased endurance and perform poorly on the rota-rod test or when hanging from a taut wire, indicating poor coordination and increased fatigue (PubMed:14722618). Mutant mice display increased cytoplasmic Ca(2+) levels and increased delays in the decrease of cytoplasmic Ca(2+) back to baseline levels after stimulation of hippocampus neurons (PubMed:21593315). They show impaired synaptic transmisison, impaired long-term potentiation, impaired learning and memory (PubMed:21593315). Besides, mutant mice display a decreased size of the spinal cord, decreased myelination, decreased numbers of oligodendrocytes and increased numbers of oligodendrocyte precursor cells (PubMed:21959935). Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC8 subfamily.