Disease relevance of FXYD1

• In vitro 14-3-3 binding assays indicated that PLM was phosphorylated following ischemia [1].
• CONCLUSIONS: Irrespective of age, obesity, and daytime sleepiness, patients with untreated PLM or IPD are more likely to experience clinically significant psychological difficulties than those with either OSA or PI [2].
• Two of 13 children with PLM > 5 per hour and no evidence of obstructive sleep apnea had attention-deficit/hyperactivity disorder [3].
• Canonical Discriminant Function Analysis was employed, which resulted in four clinical-diagnostic scales: SA for sleep apnea, NAR for narcolepsy, PSY for psychiatric sleep disorder and PLM for periodic limb movement disorder [4].
• A high prevalence of RLS or PLM (primary and secondary) has not been reported before in sarcoidosis [5].

Psychiatry related information on FXYD1

• Polysomnography, performed prior and at the end of melatonin treatment, demonstrated a significant reduction of investigated movement parameters, such as PLMs, PLM index, PLMs with arousals and PLM-arousal index [6].
• Logistic regression indicated that even after statistically controlling for these three diagnostic covariates, MMPI elevation was more likely among PLM and IPD patients than OSA or PI patients (all ps<.05) [2].
• Moreover restless legs (RLS) were reported by 52% of the patients (45% in OSA; 71% in PLM; 47% in others) [5].
• At the descriptive level, in PLMD clonazepam improved PLM during time in bed, REM and wakefulness and showed more significant changes in various sleep and awakening measures than in RLS patients, though there were no significant inter-group differences [7].
• We postulate that rather than a direct relationship between ADHD and PLMD, this link may be mediated by the presence of reduced REM sleep and more importantly by the sleep fragmentation associated with PLM-induced arousals [8].

High impact information on FXYD1

• We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM [9].
• Role of fxyd proteins in ion transport [10].
• Although effects of FXYD proteins on parameters such as K(1/2)Na(+), K(1/2)K(+), K(m)ATP, and V(max) are modest, usually twofold, these effects may have important long-term consequences for homeostasis of cation balance [10].
• Stoichiometric association of PLM with NKA occurs posttranslationally either in the Golgi or the plasma membrane [11].
• Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death [12].

Chemical compound and disease context of FXYD1

• At 10 Gy with 15 mg PLM and 1,250 mg 5-FU, grade 1 mucositis (redness of the oral mucosa) was induced in 14 patients in the control group and five patients in the Azelastine group [13].
• At 20 Gy with 30 mg PLM and 2,500 mg 5-FU, grade 2 (erosion with mild irritation) and grade 3 (extensive erosion with marked irritation) stomatitis were observed in 9 and 3 of the control patients and 5 and 1 in the Azelastine group, respectively [13].

Biological context of FXYD1

• We hypothesize that PLM interacts with alpha1/His10-beta1 subunits at multiple locations, the different functional effects depending on the degree of phosphorylation at Ser68 [14].
• The gene structure of FXYD family members suggests assembly from protein domain modules and gene duplication [15].
• Thus, tissue- and isozyme-specific interaction of Na,K-ATPase with FXYD proteins contributes to proper handling of Na+ and K+ by the Na,K-ATPase, and ensures correct function in such processes as renal Na+-reabsorption, muscle contraction, and neuronal excitability [16].
• The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression [17].
• Human PLM appears to be a unique gene localized on chromosome 19q13 [18].

Anatomical context of FXYD1

• FXYD1 or phospholemman, mainly expressed in heart and skeletal muscle increases the apparent affinity for intracellular Na(+) of Na, K-ATPase and may thus be important for appropriate muscle contractility [19].
• A lipid-soluble cysteine-cysteine bifunctional reagent, dibromobimane, cross-links CHIF to alpha in colonic membranes but not gamma or PLM to alpha in kidney or heart membranes, respectively [20].
• In detergent-solubilized HeLa cell membranes, dibromobimane cross-links wild-type CHIF to alpha but not the C49F mutant, and also the corresponding F36C mutant but not wild-type gammab, and F48C but not wild-type PLM [20].
• We show that expression of Mat-8 in Xenopus oocytes induces hyperpolarization-activated chloride currents similar to those induced by PLM expression [21].
• Here, we report that immunoreactivity for phospholemman (FXYD1), a single-span membrane protein homologous to the gamma (gamma) sub-unit of the Na,K-ATPase, is found in the kidney in EM cells with the Na,K-ATPase beta2-subunit and in cortical blood vessels and the afferent arteriole with Na,K-ATPase alpha2 and beta2 [22].

Associations of FXYD1 with chemical compounds

• The intracellular NO and O2(-) levels were increased up to about 110-120% and 140-180% of the control levels, respectively, after the treatment of OSC-4 cells with 5-FU (100 microg/ml), PLM (10 microg/ml), CDDP (10 microg/ml), or gamma-rays (20 Gy) [23].
• Descriptive data analysis demonstrated at the confirmatory level concerning three target variables that - as compared with placebo - clonazepam significantly improved objective sleep efficiency and subjective sleep quality in both patient groups, but failed to reduce the index PLM/h of sleep [7].
• In lipid bilayers, PLM forms ion channels selective for Cl-, K+, and taurine [24].
• Acute L-dopa/benserazide significantly (p < 0.001) and markedly (75%) decreased the target variable PLM/h of sleep as well as all other RLS/PLM variables, but failed to improve objective sleep efficiency and subjective sleep quality in comparison to placebo [25].
• In this study we investigated the possible effects of blueberries (BLU), blackberries (BLK), plums (PLM), mangoes (MAN), pomegranate juice (POJ), watermelon juice (WMJ) and cranberry juice (CBJ) on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in Fisher 344 male rats [26].

Physical interactions of FXYD1

• We conclude that PLM interacted with the intracellular loop of NCX1, most likely at residues 218-358 [27].

Other interactions of FXYD1

• Moreover, a mutation in FXYD2 has been linked to cases of human hypomagnesemia, indicating that perturbations in the regulation of Na-K-ATPase by FXYD proteins may be critically involved in pathophysiological states [28].
• FXYD3 expressed in stomach, colon, and numerous tumors also modulates the transport properties of Na, K-ATPase but it has a lower specificity of association than other FXYD proteins and an unusual membrane topology [19].
• The mammalian FXYD proteins FXYD1 through FXYD7 exhibit tissue-specific distribution [16].
• In membranes co-expressing alpha1/His10-beta1 with PLM the K0.5 of Na+ ions was also reduced, compared with the control, excluding the possibility that detergent or lipid in purified complexes compromise functional interactions [14].
• Further analysis using protein constructs of GST fused to various segments of the intracellular loop of NCX1 suggest that PLM bound to residues 218-371 and 508-764 but not 371-508 [27].

Analytical, diagnostic and therapeutic context of FXYD1

• The molecular masses of the purified recombinant FXYD proteins, determined from SDS-PAGE and from MALDI TOF mass spectrometry, reflect monomeric species [29].
• Co-immunoprecipitation experiments with PLM and split exchangers suggest that PLM associated with the N-terminal domain of NCX1 when it contained intracellular loop residues 218-358 [27].
• Site-directed mutagenesis of residues within the cytoplasmic domain of PLM indicated that a negative charge at Ser69 is necessary to shift the localization of PLM to the plasma membrane [30].
• Confocal immunofluorescence images using canine-specific PLM antibodies demonstrated that the exogenous PLM or its mutants were correctly targeted to sarcolemma, t-tubules, and intercalated discs, with little to none detected in intracellular compartments [31].
• Compared with wild-type myocytes, Western blots indicated total absence of PLM but no changes in Na(+)/Ca(2+) exchanger, sarcoplasmic reticulum (SR) Ca(2+)-ATPase, alpha(1)-subunit of Na(+)-K(+)-ATPase, and calsequestrin levels in PLM-null myocytes [32].

References