Tratamiento de las alteraciones de conducta secundarias a trastornos mentales comórbidos en la discapacidad intelectual / Treatment of behavioural symptoms due to comorbid mental disorders in intellectual disability

A lo largo de todas las etapas evolutivas, las personas con discapacidad intelectual pueden presentar trastornos psiquiátricos comórbidos, que a menudo son secundarios a sus déficits intelectivos y a las dificultades en sus capacidades adaptativas a los diferentes entornos que forman parte de sus vidas. Estas comorbilidades psiquiátricas cursan en ocasiones con alteraciones de conducta de difícil manejo, tanto con psicoterapia como con tratamientos farmacológicos. La medicación puede ser esencial para el control de alteraciones de conducta y otros síntomas asociados. Actualmente carecemos de guías clínicas específicas, de recomendaciones farmacológicas con la suficiente evidencia científica y de medicamentos con indicaciones expresas para abordar estos síntomas en pacientes con discapacidad intelectual. Este artículo de revisión tiene como objetivo resumir un conjunto de recomendaciones relacionadas con el uso de psicofármacos en este grupo poblacional

Throughout all evolutionary stages, people with intellectual disabilities (ID) may present with comorbid psychiatric disorders, which are often secondary to their intellectual deficits, and to the difficulties they face in their ability to adapt to the different environments that are part of their lives. These psychiatric comorbidities sometimes result in behavioral problems that are difficult to handle, both with psychotherapy and with pharmacological treatments. Medication can be essential for the control of behavioral disorders, and other associated symptoms. We currently lack specific clinical guidelines, pharmacological recommendations based on sufficient scientific evidence, and drugs with express indications for these symptoms in patients with ID. This review article aims to summarize a set of recommendations related to the use of psychiatric drugs in this population group

Antibody-mediated inhibition of EGFR reduces phosphate excretion and induces hyperphosphatemia and mild hypomagnesemia in mice.

Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg2+ balance in patients and only have a mild effect on Mg2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (Pi) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at Pi excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg2+ and/or Pi in the kidney remains controversial. Here, we inject mice with the anti-EGFR monoclonal antibody ME-1 for 2 weeks and observe a significant increase in serum Pi and mild hypomagnesemia, but no changes in Pi or Mg2+ excretion. In contrast, a single injection of ME-1 resulted in hyperphosphatemia and a significant reduction in Pi excretion 2 days after treatment, while no changes in serum Mg2+ or Mg2+ excretion were observed. Dietary Mg2+ deprivation is known to trigger a rapid Mg2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME-1 did not significantly modify the response of mice to 2 days of Mg2+ deprivation. These data show that EGFR plays a significant role in regulating Pi reabsorption in the kidney PCT, but suggest only a minor role in long-term regulation of Mg2+ transport in the distal convoluted tubule.

A Common Signal Patch Drives AP-1 Protein-dependent Golgi Export of Inwardly Rectifying Potassium Channels.

Nearly all members of the inwardly rectifying potassium (Kir) channel family share a cytoplasmic domain structure that serves as an unusual AP-1 clathrin adaptor-dependent Golgi export signal in one Kir channel, Kir2.1 (KCNJ2), raising the question whether Kir channels share a common Golgi export mechanism. Here we explore this idea, focusing on two structurally and functionally divergent Kir family members, Kir2.3 (KCNJ4) and Kir4.1/5.1 (KCNJ10/16), which have ∼50% amino identity. We found that Golgi export of both channels is blocked upon siRNA-mediated knockdown of the AP-1 γ subunit, as predicted for the common AP-1-dependent trafficking process. A comprehensive mutagenic analysis, guided by homology mapping in atomic resolution models of Kir2.1, Kir2.3, and Kir4.1/5.1, identified a common structure that serves as a recognition site for AP-1 binding and governs Golgi export. Larger than realized from previous studies with Kir2.1, the signal is created by a patch of residues distributed at the confluence of cytoplasmic N and C termini. The signal involves a stretch of hydrophobic residues from the C-terminal region that form a hydrophobic cleft, an adjacent cluster of basic residues within the N terminus, and a potential network of salt bridges that join the N- and C-terminal poles together. Because patch formation and AP-1 binding are dependent on proper folding of the cytoplasmic domains, the signal provides a common quality control mechanism at the Golgi for Kir channels. These findings identify a new proteostatic mechanism that couples protein folding of channels to forward trafficking in the secretory pathway.

Hyperphosphatemia, hypocalcemia and increased serum potassium concentration as distinctive features of early hypomagnesemia in magnesium-deprived mice.

Magnesium-deficient patients show dysfunctional calcium (Ca(2+)) metabolism due to defective parathyroid hormone (PTH) secretion. In mice and rats, long-term magnesium (Mg(2+)) deprivation causes hyperphosphaturia and increases fibroblast growth factor 23 (FGF23) secretion, despite normal serum phosphate (Pi) and Ca(2+). Electrolyte disturbances during early hypomagnesemia may explain the response of mice to long-term Mg(2+) deprivation, but our knowledge of electrolyte homeostasis during this stage is limited. This study compares the effect of both short- and long-term Mg(2+) restriction on the electrolyte balance in mice. Mice were fed control or Mg(2+)-deficient diets for one to three days, one week, or three weeks. Prior to killing the mice, urine was collected over 24 h using metabolic cages. Within 24 h of Mg(2+) deprivation, hypomagnesemia, hypocalcemia and hyperphosphatemia developed, and after three days of Mg(2+) deprivation, serum potassium (K(+)) was increased. These changes were accompanied by a reduction in urinary volume, hyperphosphaturia, hypocalciuria and decreased Mg(2+), sodium (Na(+)) and K(+) excretion. Surprisingly, after one week of Mg(2+) deprivation, serum K(+), Pi and Ca(2+) had normalized, showing that mineral homeostasis is most affected during early hypomagnesemia. Serum Pi and K(+) are known to stimulate secretion of FGF23 and aldosterone, which are usually elevated during Mg(2+) deficiency. Thus, the hyperphosphatemia and increased serum K(+) concentration observed during short-term Mg(2+) deprivation may help our understanding of adaptation to chronic Mg(2+) deficiency.

A tandem Di-hydrophobic motif mediates clathrin-dependent endocytosis via direct binding to the AP-2 ασ2 subunits.

Select plasma membrane proteins can be marked as cargo for inclusion into clathrin-coated pits by common internalization signals (e.g. YXXΦ, dileucine motifs, NPXY) that serve as universal recognition sites for the AP-2 adaptor complex or other clathrin-associated sorting proteins. However, some surface proteins, such as the Kir2.3 potassium channel, lack canonical signals but are still targeted for clathrin-dependent endocytosis. Here, we explore the mechanism. We found an unusual endocytic signal in Kir2.3 that is based on two consecutive pairs of hydrophobic residues. Characterized by the sequence ΦΦXΦΦ (a tandem di-hydrophobic (TDH) motif, where Φ is a hydrophobic amino acid), the signal shows no resemblance to other endocytic motifs, yet it directly interacts with AP-2 to target the Kir2.3 potassium channel into the endocytic pathway. We found that the tandem di-hydrophobic motif directly binds to the ασ2 subunits of AP-2, interacting within a large hydrophobic cleft that encompasses part of the docking site for di-Leu signals, but includes additional structures. These observations expand the repertoire of clathrin-dependent internalization signals and the ways in which AP-2 can coordinate endocytosis of cargo proteins.

Golgi export of the Kir2.1 channel is driven by a trafficking signal located within its tertiary structure.

Mechanisms that are responsible for sorting newly synthesized proteins for traffic to the cell surface from the Golgi are poorly understood. Here, we show that the potassium channel Kir2.1, mutations in which are associated with Andersen-Tawil syndrome, is selected as cargo into Golgi export carriers in an unusual signal-dependent manner. Unlike conventional trafficking signals, which are typically comprised of short linear peptide sequences, Golgi exit of Kir2.1 is dictated by residues that are embedded within the confluence of two separate domains. This signal patch forms a recognition site for interaction with the AP1 adaptor complex, thereby marking Kir2.1 for incorporation into clathrin-coated vesicles at the trans-Golgi. The identification of a trafficking signal in the tertiary structure of Kir2.1 reveals a quality control step that couples protein conformation to Golgi export and provides molecular insight into how mutations in Kir2.1 arrest the channels at the Golgi.

Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1.

Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca(2+) channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of beta-galactoside alpha2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of alpha2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.

WNK1 activates SGK1 to regulate the epithelial sodium channel.

WNK (with no lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Intronic deletions increase the expression of WNK1 in humans and cause pseudohypoaldosteronism type II, a form of hypertension. WNKs have been linked to ion carriers, but the underlying regulatory mechanisms are unknown. Here, we report a mechanism for the control of ion permeability by WNK1. We show that WNK1 activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel. Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2. This finding provides compelling evidence that this molecular mechanism contributes to the pathogenesis of hypertension in pseudohypoaldosteronism type II caused by WNK1 and, possibly, in other forms of hypertension.

Chloride secretion in a morphologically differentiated human colonic cell line that expresses the epithelial Na+ channel.

Cell line models of colonic electrolyte transport have been extensively used despite lacking some of the characteristics of native tissue. While native colonic crypts absorb or secrete NaCl, immortalized cell lines only retain the secretory phenotype. In the present study we have characterized functionally and molecularly, vectorial fluid and electrolyte transport in the morphologically differentiated human colonic cell line LIM1863. LIM1863 cells form morphologically differentiated organoids resembling native human colonic crypts, which secrete fluid and electrolytes across the apical membrane into a centrally located lumen. Net fluid secretion was evaluated by means of morphometric measurement of lumens formed in LIM organoids in response to known secretagogues. Pharmacological profiling of the channels and transporters involved in fluid and electrolyte transport showed that net fluid transport requires Cl- uptake across the basolateral membrane through a Na(+)-K(+)-2Cl- cotransporter (NKCC1) and its subsequent exit across an apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Similar to the native colon, net Cl- secretion in the LIM1863 cell line is activated by cAMP-mediated agonists. Carbachol, a Ca(2+)-mediated agonist, does not induce net Cl- secretion but modulates the cAMP-activated response. Expression of chloride channels (CFTR and the Ca(2+)-dependent Cl- channel, ClCa1), potassium channels (KCNN4 and KCNQ1), epithelial Na+ channel (ENaC) alpha, beta and gamma subunits and ion transporters (NKCC1; anion exchanger, AE2; Na+/H+ exchangers, NHE1-3) was detected by RT-PCR and Western blot in the case of ENaC. Based on this evidence we propose that LIM1863 cells provide a unique model for studying CFTR-dependent Cl- secretion in a morphologically differentiated human colonic crypt cell line that also expresses ENaC.

Evidence for endocytosis of ROMK potassium channel via clathrin-coated vesicles.

ROMK channels are present in the cortical collecting ducts of kidney and are responsible for K(+) secretion in this nephron segment. Recent studies suggest that endocytosis of ROMK channels is important for regulation of K(+) secretion in cortical collecting ducts. We investigated the molecular mechanisms for endocytosis of ROMK channels expressed in Xenopus laevis oocytes and cultured Madin-Darby canine kidney cells. When plasma membrane insertion of newly synthesized channel proteins was blocked by incubation with brefeldin A, ROMK currents decreased with a half-time of ~6 h. Coexpression with the Lys44-->Ala dominant-negative mutant dynamin, but not wild-type dynamin, reduced the rate of reduction of ROMK in the presence of brefeldin A. Mutation of Asn371 to Ile in the putative NPXY internalization motif of ROMK1 abolished the effect of the Lys44-->Ala dynamin mutant on endocytosis of the channel. Coimmunoprecipitation study and confocal fluorescent imaging revealed that ROMK channels associated with clathrin coat proteins in Madin-Darby canine kidney cells. These results provide compelling evidence for endocytosis of ROMK channels via clathrin-coated vesicles.