Functional Roles of the α Isoforms of the Na,K‐ATPase

: The Na,K-ATPase is composed of two subunits, α and β, and each subunit consists of multiple isoforms. In the case of α, four isoforms, α1, α2, α3, and α4 are present in mammalian cells. The distribution of these isoforms is tissue- and developmental-specific, suggesting that they may play specific roles, either during development or coupled to specific physiological processes. In order to understand the functional properties of each of these isoforms, we are using gene targeting, where animals are produced lacking either one copy or both copies of the corresponding gene or have a modified gene. To date, we have produced animals lacking the α1 and α2 isoform genes. Animals lacking both copies of the α1 isoform gene are not viable, while animals lacking both copies of the α2 isoform gene make it to birth, but are either born dead or die very soon after. In the case of animals lacking one copy of the α1 or α2 isoform gene, the animals survive and appear healthy. Heart and EDL muscle from animals lacking one copy of the α2 isoform exhibit an increase in force of contraction, while there is reduced force of contraction in both muscles from animals lacking one copy of the α1 isoform gene. These studies indicate that the α1 and α2 isoforms carry out different physiological roles. The α2 isoform appears to be involved in regulating Ca2+ transients involved in muscle contraction, while the α1 isoform probably plays a more generalized role. While we have not yet knocked out the α3 or α4 isoform genes, studies to date indicate that the α4 isoform is necessary to maintain sperm motility. It is thus possible that the α2, α3, and α4 isoforms are involved in specialized functions of various tissues, helping to explain their tissue- and developmental-specific regulation.