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

Abstract

The Na,K-ATPase is composed of two subunits, alpha and beta, and each subunit consists of multiple isoforms. In the case of alpha, four isoforms, alpha1, alpha2, alpha3, and alpha4 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 alpha1 and alpha2 isoform genes. Animals lacking both copies of the alpha1 isoform gene are not viable, while animals lacking both copies of the alpha2 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 alpha1 or alpha2 isoform gene, the animals survive and appear healthy. Heart and EDL muscle from animals lacking one copy of the alpha2 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 alpha1 isoform gene. These studies indicate that the alpha1 and alpha2 isoforms carry out different physiological roles. The alpha2 isoform appears to be involved in regulating Ca(2+) transients involved in muscle contraction, while the alpha1 isoform probably plays a more generalized role. While we have not yet knocked out the alpha3 or alpha4 isoform genes, studies to date indicate that the alpha4 isoform is necessary to maintain sperm motility. It is thus possible that the alpha2, alpha3, and alpha4 isoforms are involved in specialized functions of various tissues, helping to explain their tissue- and developmental-specific regulation.

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

“…The Atp1a3a transcript was also abundant in the spinal cord and, to a lesser extent, in the heart. The latter observation is consistent with previous studies demonstrating ATP1␣ 3 expression in the neonatal, but not adult, rat heart (40,41).…”

“…In mammals, the four ␣ (␣ 1 , ␣ 2 , ␣ 3 , and ␣ 4 ) isoforms display distinct tissue-specific expression patterns (2,3). The ␣ 3 isoform (ATP1␣ 3 ) is expressed in brain, eye, ear, muscle, cartilage, uterus, placenta, and heart (4 -7). In the brain, the ATP1␣ 3 subunit is present exclusively in neurons (8).…”

“…regulation of cell volume, pH, Na ϩ -coupled secondary transport of molecules and neurotransmitters, and the excitability of muscle and neuronal cells (1,2). In mammals, the four ␣ (␣ 1 , ␣ 2 , ␣ 3 , and ␣ 4 ) isoforms display distinct tissue-specific expression patterns (2,3). The ␣ 3 isoform (ATP1␣ 3 ) is expressed in brain, eye, ear, muscle, cartilage, uterus, placenta, and heart (4 -7).…”

Familial Hemiplegic Migraine

“…62 In contrast with the ␣ 1 isoform, which maintains generalized cellular homeostasis of Na ϩ and K ϩ as a housekeeping role, the ␣ 2 isoform plays more specific roles by colocalization with various ion transporters. 75 In the murine brain, the ␣ 2 Na ϩ ,K ϩ -ATPase is expressed primarily in neurons during embryonic development and at the time of birth, and primarily in glial cells in the adult. [76][77][78] Impaired clearance of neurotransmitters and enhanced neuronal excitation in the amygdala and pyriform cortex were shown in Atp1a2 Ϫ/Ϫ mice at the embryonic stage.…”

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

“…Além disso, se usada agudamente em humanos saudáveis, a infusão desse digitálico é capaz de induzir o aumento da resistência vascular periférica, a redução do fluxo sanguíneo e a elevação da pressão arterial (MASON;BRAUNWALD, 1964;SCHULTE et al, 1987). Dessa forma, como apontado acima, o aumento plasmático desse digitálico é capaz de levar a um quadro que favorece o estado hipertensivo.Por sua vez, o principal sítio de ação da OUA é a Na + , K + ATPase, enzima expressa em todas as células de mamíferos e que, em sua via clássica, utiliza a energia da hidrólise do trifosfato de adenosina (ATP) para realizar o transporte de 3íons Na + e 2 íons K + através da membrana (Figura 3A) (BOLDYREV, 2000; KAPLAN, 2002; SKOU, 2004 Em mamíferos, quatro tipos de subunidades α (α1, α2, α3 e α4) e três tipos de subunidades β (β1, β2 e β3) são expressas em diferentes combinações e também em tipos específicos de células, sendo reguladas pelo desenvolvimento (BLANCO, 2005;LINGREL et al, 2003;MOBASHERI et al, 2000;SWEADNER, 1991).Adicionalmente, uma das maiores diferenças cinéticas entre as isoformas α é sua sensibilidade única à OUA. Em roedores, enquanto a isoforma α1 é altamente resistente à inibição da OUA, α2, α3 e α4 são progressivamente mais sensíveis a essa mesma inibição (BLANCO, 2005;O'BRIEN, 1994;SWEADNER, 1993).…”