Jgp_201711899 969..974

In the 1980s, medical research set its focus more and more on molecular aspects of diseases, and it was not long until an individual mutation in a single protein species was found to cause the complete phenotype of a disease. Unsurprisingly, ion channels were among those culprits. Significant public attention was aroused when mutations in the (then appropriately named) cystic fibrosis transmembrane conductance regulator (CFTR)—a chloride channel—were identified as initiators of cystic fibrosis (Riordan et al., 1989). Within years, an entire zoo of channel-dependent diseases was discovered, and the term “channelopathy” was introduced to describe them. It is perhaps not a surprise, then, to find that mutations in ion pumps also cause disease. But because cells get along with about a dozen of ion pumps, in contrast to hundreds of channels, the number of pump-induced diseases is rather limited and the notation “pumpopathy” will probably not be needed to embrace them. In this issue of The Journal of General Physiology, Meyer and colleagues investigate one such pump-induced disease and define the molecular mechanism that underlies it. The Na,K-ATPase—a member of the P-type ATPase family—is an essential ion transporter in virtually all animal cells. This pump exists in several isoforms to handle the specific metabolic needs of each cell type. Numerous clinical conditions have been correlated with modified Na,K-ATPase activity for decades and are mainly caused by alteration of endogenous or xenobiotic factors (Rose and Valdes, 1994). In 2004, however, a specific mutation in the α2 isoform of the Na,K-ATPase was found to cause familial hemiplegic migraine (Swoboda et al., 2004), and in the years that followed, further mutations were identified to cause various forms of migraine (Friedrich et al., 2016). More recently, it has been found that mutations in the neuron-specific Na,K-ATPase α3 subunit are linked to rapid-onset dystonia Parkinsonism (Shrivastava et al., 2015) and that the α3 subunit may play also a role in the neurodegeneration of Alzheimer patients (Ohnishi et al., 2015). There is another disease, primary aldosteronism, which causes secondary hypertension by overproduction of aldosterone, that is provoked—among other reasons—by single mutations of the α1 isoform of the Na,K-ATPase in adenomas within the zona glomerulosa of the adrenal cortex. In recent years, mutations of five residues in the α1 subunit have been found to cause overproduction of aldosterone: G99R, L104R, delF100-L104, V332G, and EETA963S (Azizan et al., 2013; Beuschlein et al., 2013; Williams et al., 2014). The chain of events that lead to aldosterone production in the adrenal cortex begins with transient membrane depolarizations initiated by angiotensin II or hyperkalemia followed by an increase in intracellular Ca concentration. As a second messenger, intracellular Ca triggers increased transcription of the CYP11B2 gene that encodes aldosterone synthase, and so leads to an enhancement of aldosterone production (Fig. 1 A). In the case of hyperaldosteronism, as it is found in aldosterone-producing adenomas, constitutive aldosterone production is detected without physiological triggers. Assuming that the intracellular chain of events that begins with increased Ca is unchanged, the pathological culprit has to be part of the mechanism that leads to this boost of Ca. There are several possible mechanisms that could produce such an enhanced Ca concentration: Mutations of Ca or K channels, the plasma membrane Ca-ATPase (PMCA), or the Na,K-ATPase. Modified Ca channels or gradually malfunctioning Ca-ATPases could directly lead to enhanced Ca concentrations. Altered K channels could cause loss of cytoplasmic K, which would depolarize the resting potential and thus provoke increased opening of voltage-dependent Ca channels. However, when mutations of the Na,K-ATPase are the initiators, it must be an indirect way that triggers the gain of intracellular Ca. But even if one restricts the investigation to the Na,K-ATPase, it turns out that the underlying molecular mechanism is not just one clear-cut process, as it is revealed in the paper of Meyer et al. (2017). A couple of years ago, studies of the first three mutations causing primary aldosteronism, L104R, delF100-L104, V332G, were performed with cells from adenoma primary cultures and COS cells transfected with cDNA encoding wild-type Na,K-ATPase or one of these mutations. The crucial finding was that these mu-