Medicines policy, access and use in Mexico: a systematic literature review 2000-2022.

Background: Research on medicines access and use is heterogeneous and can be challenging for decision-makers to interpret. Pharmaceutical policy is an additional component for study and is the foundation for the promotion of access and use of medicines. This systematic review summarizes findings from the literature on medicines policy, access and use over the past two decades in Mexico and identifies research gaps that should be addressed. Methods: A systematic review of the literature published between 2000 and 2022 was conducted to identify publications on medicines policy, access and use in Mexico. The study followed PRISMA Statement guidelines 2020. A narrative review including content analysis was conducted. Results: A total of 5057 articles were reviewed, of which 77 fit the inclusion criteria. Studies described the lack of an explicit national policy, a misalignment between the legal framework and reinforcement incentives, deficient policy documentation at the national level, and the absence of necessary medicines regulation and transparency. In terms of access to medicines, challenges related to supply, selection, acquisition, distribution and expenditure were noted. Regarding medicine use, key study findings included a lack of adherence to standard treatment guidelines, dispensing, lack of reliable information on medicines, lack of treatment adherence and harmful self-medication. Conclusion: The appropriate use of medicines and adequate access to them are priority topics for the formulation of Mexican pharmaceutical policy. It is critical that further research includes longitudinal studies of medicine access and use, and the consideration of studying the private sector as well as new methodological approaches. Many reported challenges related to access to and use of medicines have persisted across decades, suggesting a lack of effective research-to-practice knowledge transfer and policy implementation.This article is part of the Hospital pharmacy, rational use of medicines and patient safety in Latin America Special Issue: https://www.drugsincontext.com/special_issues/hospital-pharmacy-rational-use-of-medicines-and-patient-safety-in-latin-america/.

Single-Nucleus Transcriptional Profiling of GAD2-Positive Neurons From Mouse Lateral Habenula Reveals Distinct Expression of Neurotransmission- and Depression-Related Genes.

Background: Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. Methods: A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic (gamma-aminobutyric acidergic)-synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons, and they coexpress the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single-nucleus RNA sequencing. Results: Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb coexpress markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder, which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein netrin-G2 as a marker of LHb GAD2+/VGLUT2+ neurons and a gene product that may contribute to their target projections. Conclusions: These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.

Single-nucleus transcriptional profiling of GAD2-positive neurons from mouse lateral habenula reveals distinct expression of neurotransmission- and depression-related genes.

Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons and they co-express the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single nuclear RNA sequencing (FANS-snRNAseq). Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb co-express markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder (MDD), which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein Netrin-G2 as a marker of LHb GAD2+/VGLUT+ neurons and a gene product that may contribute to their target projections. These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.

Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine.

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we assessed expression of PV-enriched, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants to explore the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

Streptomyces spiramenti sp. nov., isolated from a deep-sea microbial mat.

Strain 5675061T was isolated from a deep-sea microbial mat near hydrothermal vents within the Axial Seamount caldera on the Juan de Fuca Ridge (NE Pacific Ocean) and was taxonomically evaluated using a polyphasic approach. Morphological and chemotaxonomic properties are consistent with characteristics of the genus Streptomyces: aerobic Gram-stain-positive filaments that form spores, L,L-diaminopimelic acid in whole-cell hydrolysates, and iso-C16:0 as the major fatty acid. Phylogenetic analysis, genomic, and biochemical comparisons show close evolutionary relatedness to Streptomyces lonarensis NCL716T, S. bohaiensis 11A07T, and S. otsuchiensis OTB305T but genomic relatedness indices identify strain 5675061T as a distinct species. Based on a polyphasic characterization, identifying differences in genomic and taxonomic data, strain 5675061T represents a novel species, for which the name Streptomyces spiramenti sp. nov. is proposed. The type strain is 5675061T (=LMG 31896T = DSM 111793T).

Pharmacy practice in Latin America: a review of published literature, 2017-2021.

Background: Pharmacy practice (PP) research is a new discipline that studies the scope of interventions and health services performed by pharmacists. Information on PP in Latin America is available; however, to date, it has not been methodically analysed. It is critical to understand the current level of evolution of pharmaceutical activities to support evidence-based decision-making. Methods: We performed a review of PP literature published in five databases, of which two were international and three were focused on Latin America. The data obtained were qualitative, such that the strategies used for data search and collection were structured by PRISMA guidelines, and data synthesis and analysis were conducted through a narrative review. Results: Of the 1863 articles found in the initial search, 108 were included in the final analysis. The majority of these were conducted in Brazil (n=73, 74%) and Colombia (n=14, 13%). The interventions and services most frequently reported were dispensing (n=24, 22%), clinical pharmacy services (n=21, 19%) and pharmaceutical care (n=21, 19%). Most studies focused on only one key strategic area (n=94, 87%), specifically on health services provision. Conclusion: PP in Latin America follows worldwide trends to some extent with regard to the inclusion of clinical pharmacy and pharmaceutical care. However, the region also demonstrates particularities, including the heterogenous level of development amongst its countries. It is vital for Latin American pharmacists to publish their activities, interventions and services in order to generate a solid evidence base to evaluate practice and support informed decision-making.

Draft Genome Sequence of Streptomyces sp. Strain ventii, Isolated from a Microbial Mat near Hydrothermal Vents within the Axial Seamount in the Pacific Ocean, and Resequencing of the Type Strains Streptomyces lonarensis NCL 716 and Streptomyces bohaiensis 11A07.

The draft genome of Streptomyces sp. strain ventii, an environmental isolate recovered from deep-sea hydrothermal vents in the Pacific Ocean, is presented along with the resequenced draft genomes of the type strains Streptomyces bohaiensis 11A07 and Streptomyces lonarensis NCL 716.

Athletic trainers' unique clinical and teamwork skills contribute on the frontlines during the COVID-19 pandemic: A discussion paper.

Crises such as pandemics create stresses on the health-care system that often produce innovation and changes in roles and delivery methods. In the current pandemic, and with the interruption of organized sport activities, athletic trainers have moved beyond traditional hierarchies and scopes of practice to roles that fully leverage their knowledge, skills, and abilities. Through background literature, discussion, and examples, this paper shows how the Athletic Training profession has made an impact in the response to the COVID-19 pandemic. The authors also present key questions as the health-care system moves forward through these challenges. In the future, there could be a new paradigm in the health-care system that values athletic trainers on interprofessional teams which focus on health and wellness to improve outcomes for individuals and society.

Morphometry and meristics of two species of Ictalurus (Siluriformes: Ictaluridae), native catfishes of Sierra Madre Occidental, Mexico

Introduction: Morphotypes of native catfish of the genus Ictalurus (Siluriformes: Ictaluridae) are known to occur in allopatry in the northern Sierra Madre Occidental of Mexico, with only the Yaqui catfish (Ictalurus pricei) taxonomically described. Recent genetic analysis of these morphotypes has revealed the monophyly of the I. pricei complex, which indicates Ictalurus sp. from the Culiacán River and San Lorenzo River basins as its nearest genetic relative and recognizes as an evolutionarily significant unit the Culiacán River and San Lorenzo River morphotypes. Objective: To compare the meristic and morphometric characteristics of the catfish of the Culiacán River basin with its nearest genetic relative, the Yaqui catfish, in order to determine the presence of distinctive morphological characters that support genetic evidence previously reported for these morphotypes. Methods: Catfish specimens were collected during various field expeditions (1990-2012) to remote sites of the Sierra Madre Occidental and conducted in the Yaqui River and Culiacán River basins with the purpose of morphological comparison. Forty-five morphological characters (40 morphometric and five meristic) were examined in 76 adult specimens - 52 Ictalurus sp. and 24 Ictalurus pricei. Three groups were subject to a discriminant function analysis (DFA), including two Ictalurus sp. groups from the Humaya River and Tamazula River sub-basins, representing the Culiacán River basin, and one I. pricei group representing the Yaqui River basin. The standardized measurements and meristic data of the catfish morphotypes were compared by means of DFA. Results: The DFA revealed 12 characters to be significantly different (P< 0.01) among the groups compared. The morphological characters separating the Ictalurus sp. (Culiacán River basin) from the Yaqui catfish were associated with lower anal, pelvic and pectoral fin ray numbers, shorter head and predorsal lengths, shorter longest lateral barbel and longest dorsal ray lengths and a narrower premaxilar dentary plate; and finally longer distances in Ictalurus sp. for dorsal-fin origin to last anal-fin ray base and dorsal-fin origin to posterior end of the adipose fin base. The standardized coefficients for canonical variables 1 and 2 accounted for 85.6 % and 14.4 % of the total variation, respectively. Conclusions: The distinctive morphological characters of the Ictalurus sp. found in the Culiacán River basin, combined with the known mitochondrial evidence for this morphotype, identify it as an evolutionarily significant unit that requires description as a new species based on taxonomical protocols.

Introducción: Morfotipos de bagres nativos del género Ictalurus (Siluriformes: Ictaluridae) se distribuyen de manera alopátrica en el norte de la Sierra Madre Occidental, de los cuales solo el bagre Yaqui (Ictalurus pricei) ha sido taxonómicamente descrito. Análisis genéticos recientes de esos morfotipos han revelado la monofilia del complejo I. pricei, que incluyó a Ictalurus sp. de las cuencas de los ríos Culiacán y San Lorenzo como su pariente genético más cercano, además del reconocimiento de los morfotipos de los ríos Culiacán and San Lorenzo como una unidad evolutivamente significativa. Objetivo: Comparar características merísticas y morfométricas del bagre de la cuenca del río Culiacán con su pariente genético más cercano, el bagre Yaqui, con el propósito de determinar la presencia de caracteres morfológicos distintivos en apoyo a evidencia genética previamente reportada para esos morfotipos. Métodos: Especímenes de bagres fueron recolectados durante varias expediciones de campo (1990-2012) en sitios remotos de la Sierra Madre Occidental en las cuencas de los ríos Yaqui y Culiacán para comparación morfológica. Cuarenta y cinco caracteres morfológicos (40 morfométricos y cinco merísticos) fueron examinados en 76 especímenes adultos (52 de Ictalurus sp. y 24 de Ictalurus pricei). Medidas corporales estandarizadas y datos merísticos de los morfotipos de bagres estudiados fueron comparados por medio de un análisis de función discriminante (AFD). Resultados: El AFD arrojó 12 caracteres significativamente diferentes (P< 0.01) entre los grupos comparados. Los caracteres morfológicos que distinguen al bagre del río Culiacán del bagre Yaqui, estuvieron asociados con un menor número de radios anales, pélvicos y pectorales, así como dimensiones más pequeñas para la longitud de la cabeza, longitud predorsal, longitud de la barbilla lateral más larga, longitud del radio dorsal más largo y una menor anchura de la placa dentaria premaxilar; y finalmente, dimensiones mayores en Ictalurus sp. (cuenca del río Culiacán) para distancias como origen de aleta dorsal a la base del último radio anal y origen de aleta dorsal a conexión posterior de aleta adiposa. Los coeficientes estandarizados para las variables canónicas 1 y 2 explicaron el 85.6 y 14.4 % de la variación total, respectivamente. Conclusiones: Los caracteres morfológicos distintivos de Ictalurus sp. de la cuenca del río Culiacán, en combinación con la evidencia mitocondrial conocida para este mismo morfotipo, permite reconocerlo como una unidad evolutivamente significativa y que requiere ser descrita como una especie nueva bajo los protocolos taxonómicos.

A striatal interneuron circuit for continuous target pursuit.

Most adaptive behaviors require precise tracking of targets in space. In pursuit behavior with a moving target, mice use distance to target to guide their own movement continuously. Here, we show that in the sensorimotor striatum, parvalbumin-positive fast-spiking interneurons (FSIs) can represent the distance between self and target during pursuit behavior, while striatal projection neurons (SPNs), which receive FSI projections, can represent self-velocity. FSIs are shown to regulate velocity-related SPN activity during pursuit, so that movement velocity is continuously modulated by distance to target. Moreover, bidirectional manipulation of FSI activity can selectively disrupt performance by increasing or decreasing the self-target distance. Our results reveal a key role of the FSI-SPN interneuron circuit in pursuit behavior and elucidate how this circuit implements distance to velocity transformation required for the critical underlying computation.

Enhancer Histone Acetylation Modulates Transcriptional Bursting Dynamics of Neuronal Activity-Inducible Genes.

Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. Exactly how histone acetylation modulates transcription of these genes has remained unknown. We used single-cell in situ transcriptional analysis to show that Fos and Npas4 are transcribed in stochastic bursts in mouse neurons and that membrane depolarization increases mRNA expression by increasing burst frequency. We then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins to mimic or block activity-induced histone acetylation locally at enhancers. Adding histone acetylation increased Fos transcription by prolonging burst duration and resulted in higher Fos protein levels and an elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency and impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus, activity-inducible histone acetylation tunes the transcriptional dynamics of experience-regulated genes to affect selective changes in neuronal gene expression and cellular function.

Jizanpeptins, Cyanobacterial Protease Inhibitors from a Symploca sp. Cyanobacterium Collected in the Red Sea.

Jizanpeptins A-E (1-5) are micropeptin depsipeptides isolated from a Red Sea specimen of a Symploca sp. cyanobacterium. The planar structures of the jizanpeptins were established using NMR spectroscopy and mass spectrometry and contain 3-amino-6-hydroxy-2-piperidone (Ahp) as one of eight residues in a typical micropeptin motif, as well as a side chain terminal glyceric acid sulfate moiety. The absolute configurations of the jizanpeptins were assigned using a combination of Marfey's methodology and chiral-phase HPLC analysis of hydrolysis products compared to commercial and synthesized standards. Jizanpeptins A-E showed specific inhibition of the serine protease trypsin (IC50 = 72 nM to 1 µM) compared to chymotrypsin (IC50 = 1.4 to >10 µM) in vitro and were not overtly cytotoxic to HeLa cervical or NCI-H460 lung cancer cell lines at micromolar concentrations.

Chromatin Regulation of Neuronal Maturation and Plasticity.

Neurons are dynamic cells that respond and adapt to stimuli throughout their long postmitotic lives. The structural and functional plasticity of neurons requires the regulated transcription of new gene products, and dysregulation of transcription in either the developing or adult brain impairs cognition. We discuss how mechanisms of chromatin regulation help to orchestrate the transcriptional programs that underlie the maturation of developing neurons and the plasticity of adult neurons. We review how chromatin regulation acts locally to modulate the expression of specific genes and more broadly to coordinate gene expression programs during transitions between cellular states. These data highlight the importance of epigenetic transcriptional mechanisms in postmitotic neurons. We suggest areas where emerging methods may advance understanding in the future.

Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required For Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference.

To determine the requirement for parvalbumin (PV) expressing GABAergic interneurons of the nucleus accumbens (NAc) in the behavioral adaptations induced by amphetamine (AMPH), we blocked synaptic vesicle release from these neurons using Cre-inducible viral expression of the tetanus toxin light chain in male and female PV-Cre mice. Silencing PV+ interneurons of the NAc selectively inhibited the expression of locomotor sensitization following repeated injections of AMPH and blocked AMPH-induced conditioned place preference (CPP). AMPH induced significantly more expression of the activity-dependent gene Fos in both D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the NAc of PV+ interneuron silenced mice, suggesting a function for PV+ interneuron-mediated MSN inhibition in the expression of AMPH-induced locomotor sensitization and CPP. These data show a requirement for PV+ interneurons of the NAc in behavioral responses to AMPH, and they raise the possibility that modulation of PV+ interneuron function may alter the development or expression of psychostimulant-induced behavioral adaptations.

New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors.

Mandelalides A-D (1-4) are macrocyclic polyketides known to have an unusual bioactivity profile influenced by compound glycosylation and growth phase of cultured cells. The isolation and characterization of additional natural congeners, mandelalides E-L (5-12), and the supply of synthetic compounds 1 and 12, as well as seco-mandelalide A methyl ester (13), have now facilitated mechanism of action and structure-activity relationship studies. Glycosylated mandelalides are effective inhibitors of aerobic respiration in living cells. Macrolides 1 and 2 inhibit mitochondrial function similar to oligomycin A and apoptolidin A, selective inhibitors of the mammalian ATP synthase (complex V). 1 inhibits ATP synthase activity from isolated mitochondria and triggers caspase-dependent apoptosis in HeLa cells, which are more sensitive to inhibition by 1 in the presence of the glycolysis inhibitor 2-deoxyglucose. Thus, mandelalide cytotoxicity depends on basal metabolic phenotype; cells with an oxidative phenotype are most likely to be inhibited by the mandelalides.

Insulin Induces Relaxation and Decreases Hydrogen Peroxide-Induced Vasoconstriction in Human Placental Vascular Bed in a Mechanism Mediated by Calcium-Activated Potassium Channels and L-Arginine/Nitric Oxide Pathways.

HIGHLIGHTS Short-term incubation with insulin increases the L-arginine transport in HUVECs.Short-term incubation with insulin increases the NO synthesis in HUVECs.Insulin induces relaxation in human placental vascular bed.Insulin attenuates the constriction induced by hydrogen peroxide in human placenta.The relaxation induced by insulin is dependent on BKCa channels activity in human placenta. Insulin induces relaxation in umbilical veins, increasing the expression of human amino acid transporter 1 (hCAT-1) and nitric oxide synthesis (NO) in human umbilical vein endothelial cells (HUVECs). Short-term effects of insulin on vasculature have been reported in healthy subjects and cell cultures; however, its mechanisms remain unknown. The aim of this study was to characterize the effect of acute incubation with insulin on the regulation of vascular tone of placental vasculature. HUVECs and chorionic vein rings were isolated from normal pregnancies. The effect of insulin on NO synthesis, L-arginine transport, and hCAT-1 abundance was measured in HUVECs. Isometric tension induced by U46619 (thromboxane A2 analog) or hydrogen peroxide (H2O2) were measured in vessels previously incubated 30 min with insulin and/or the following pharmacological inhibitors: tetraethylammonium (KCa channels), iberiotoxin (BKCa channels), genistein (tyrosine kinases), and wortmannin (phosphatidylinositol 3-kinase). Insulin increases L-arginine transport and NO synthesis in HUVECs. In the placenta, this hormone caused relaxation of the chorionic vein, and reduced perfusion pressure in placental cotyledons. In vessels pre-incubated with insulin, the constriction evoked by H2O2 and U46619 was attenuated and the effect on H2O2-induced constriction was blocked with tetraethylammonium and iberiotoxin, but not with genistein, or wortmannin. Insulin rapidly dilates the placental vasculature through a mechanism involving activity of BKCa channels and L-arginine/NO pathway in endothelial cells. This phenomenon is related to quick increases of hCAT-1 abundance and higher capacity of endothelial cells to take up L-arginine and generate NO.

Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels.

Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K(+) (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or ß-subunits (KChIP2 and MiRP) of K(+) channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology.

Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate.

Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates Shaker K+ channels and voltage-gated Ca2+ channels in a bimodal fashion by inhibiting voltage activation while stabilizing open channels. Bimodal regulation is conserved in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, but voltage activation is enhanced while the open channel state is destabilized. The proposed sites of PIP2 regulation in these channels include the voltage-sensor domain (VSD) and conserved regions of the proximal cytoplasmic C terminus. Relatively little is known about PIP2 regulation of Ether-á-go-go (EAG) channels, a metazoan-specific family of K+ channels that includes three gene subfamilies, Eag (Kv10), Erg (Kv11), and Elk (Kv12). We examined PIP2 regulation of the Elk subfamily potassium channel human Elk1 to determine whether bimodal regulation is conserved within the EAG K+ channel family. Open-state stabilization by PIP2 has been observed in human Erg1, but the proposed site of regulation in the distal C terminus is not conserved among EAG family channels. We show that PIP2 strongly inhibits voltage activation of Elk1 but also stabilizes the open state. This stabilization produces slow deactivation and a mode shift in voltage gating after activation. However, removal of PIP2 has the net effect of enhancing Elk1 activation. R347 in the linker between the VSD and pore (S4-S5 linker) and R479 near the S6 activation gate are required for PIP2 to inhibit voltage activation. The ability of PIP2 to stabilize the open state also requires these residues, suggesting an overlap in sites central to the opposing effects of PIP2 on channel gating. Open-state stabilization in Elk1 requires the N-terminal eag domain (PAS domain + Cap), and PIP2-dependent stabilization is enhanced by a conserved basic residue (K5) in the Cap. Our data shows that PIP2 can bimodally regulate voltage gating in EAG family channels, as has been proposed for Shaker and HCN channels. PIP2 regulation appears fundamentally different for Elk and KCNQ channels, suggesting that, although both channel types can regulate action potential threshold in neurons, they are not functionally redundant.