Edema related to treatment with psychotropic drugs.

Edema as an adverse drug reaction is a commonly underestimated yet potentially debilitating condition. This study analyzes the incidence of severe psychotropic drug-induced edema (e.g., edema affecting the face, legs, or multiple body parts and lasting for more than 1 week, or in any case necessitating subsequent diuretic use) among psychiatric inpatients. The cases under examination are derived from an observational pharmacovigilance program conducted in German-speaking countries ("Arzneimittelsicherheit in der Psychiatrie", AMSP) from 1993 to 2016. Among the 462,661 inpatients monitored, severe edema was reported in 231 cases, resulting in an incidence of 0.05%. Edema occurred more frequently in women (80% of all cases) and older patients (mean age 51.8 years). Pregabalin had the highest incidence of severe edema, affecting 1.46‰ of patients treated with pregabalin, followed by mirtazapine (0.8‰). The majority of edema cases showed a positive response to appropriate countermeasures, such as dose reduction and drug discontinuation, and resolved by the end of the observation period. While most instances of drug-induced edema are reversible, they can have a significant impact on patient well-being and potentially result in decreased treatment adherence. It is, therefore, crucial to remain vigilant regarding risk-increasing circumstances during treatment with psychotropic drugs.

Changes in emergency department utilisation in Germany before and during different phases of the COVID-19 pandemic, using data from a national surveillance system up to June 2021.

BACKGROUND: During the COVID-19 pandemic and associated public health and social measures, decreasing patient numbers have been described in various healthcare settings in Germany, including emergency care. This could be explained by changes in disease burden, e.g. due to contact restrictions, but could also be a result of changes in utilisation behaviour of the population. To better understand those dynamics, we analysed routine data from emergency departments to quantify changes in consultation numbers, age distribution, disease acuity and day and hour of the day during different phases of the COVID-19 pandemic. METHODS: We used interrupted time series analyses to estimate relative changes for consultation numbers of 20 emergency departments spread throughout Germany. For the pandemic period (16-03-2020 - 13-06-2021) four different phases of the COVID-19 pandemic were defined as interruption points, the pre-pandemic period (06-03-2017 - 09-03-2020) was used as the reference. RESULTS: The most pronounced decreases were visible in the first and second wave of the pandemic, with changes of - 30.0% (95%CI: - 32.2%; - 27.7%) and - 25.7% (95%CI: - 27.4%; - 23.9%) for overall consultations, respectively. The decrease was even stronger for the age group of 0-19 years, with - 39.4% in the first and - 35.0% in the second wave. Regarding acuity levels, consultations assessed as urgent, standard, and non-urgent showed the largest decrease, while the most severe cases showed the smallest decrease. CONCLUSIONS: The number of emergency department consultations decreased rapidly during the COVID-19 pandemic, without extensive variation in the distribution of patient characteristics. Smallest changes were observed for the most severe consultations and older age groups, which is especially reassuring regarding concerns of possible long-term complications due to patients avoiding urgent emergency care during the pandemic.

Antipsychotic drug treatment of schizophrenia in later life: Results from the European cross-sectional AMSP study.

OBJECTIVES: To investigate the relationship between patient age and the selection and dosage of antipsychotic drugs (APDs) for treatment of schizophrenia. We describe age effects for multiple individual APDs, thus allowing comparisons between drugs. METHODS: Prescription data of 32,062 inpatients with schizophrenia from 2000 to 2017 were obtained from the Drug Safety Program in Psychiatry (AMSP) database. APD selection and dosage were related to patient age with sex as an influencing variable. Moreover, a systematic search of current guideline recommendations on APD treatment in patients with schizophrenia aged ≥65 years was performed. RESULTS: Eighty percentof elderly patients (≥65 years) received a second-generation APD, most commonly risperidone. The dosage of APDs increased with age until about age 40 years, then decreased slowly at first and more steeply beyond age 55 years. The influence of age as well as sex on dosage partly differed between the individual drugs. Only one of eight schizophrenia guidelines systematically addressed specific aspects of pharmacotherapy in older adults. CONCLUSIONS: In clinical routine, age has a significant impact on selection and dosing of APDs. Information on optimising pharmacotherapy in older adults with schizophrenia from clinical trials is needed. Guidelines should be improved regarding APD therapy specifically for older adults.

SARS-CoV-2 infection dynamics in the tourism season 2020 in North Frisia, Germany.

Background: International tourist activities including air travel, holiday on cruise ships, and Après-ski parties played a prominent role in the early spread of the SARS-CoV-2 pandemic. However, the effects of national tourism on infection dynamics are unclear. Methods: Data were analyzed from the health authorities in North Frisia, the northernmost district in Germany with prominent tourist hotspots such as Sylt, Amrum, and Föhr. Data were available for the time period April 2020-November 2020. Results: During the tourist season (May-October 2020), PCR-confirmed SARS-CoV-2 case numbers were low with 0 to 10 cases per day. Case numbers rose in September and peaked end of October (2nd wave). Among the confirmed cases, 13 persons were returning travelers and none were national tourists. Overall, only a small proportion of cases were related to individuals with presumed tourist contact. Conclusion: In summer 2020, the arrival of a large number of tourists apparently did not increase local case numbers, and tourism-related outbreaks were not reported. Thus, tourism presumably did not contribute substantially to SARS-CoV-2 infection dynamics in North Frisia. However, incidences were low countrywide and protective measures were in place.

Psychotropic drug-induced hyponatremia: results from a drug surveillance program-an update.

Hyponatremia (HN) is the most common electrolyte imbalance (defined as a serum sodium concentration Na(S) of  < 130 mmol/l) and often induced by drugs including psychotropic drugs. AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicenter drug surveillance program that assesses severe or unusual adverse drug reactions (ADRs) occurring during treatment with psychotropic drugs. This study presents data from 462,661 psychiatric inpatients treated in participating hospitals between 1993 and 2016 and serves as an update of a previous contribution by Letmaier et al. (JAMA 15(6):739-748, 2012). A total of 210 cases of HN were observed affecting 0.05% of patients. 57.1% of cases presented symptomatically; 19.0% presented with severe symptoms (e.g., seizures, vomiting). HN occurred after a median of 7 days following the first dose or dose increase. Incidence of HN was highest among the two antiepileptic drugs oxcarbazepine (1.661% of patients treated) and carbamazepine (0.169%), followed by selective serotonin-norepinephrine reuptake inhibitors (SSNRIs, 0.088%) and selective serotonin reuptake inhibitors (0.071%). Antipsychotic drugs, tricyclic antidepressants, and mirtazapine exhibited a significantly lower incidence of HN. The risk of HN was 16-42 times higher among patients concomitantly treated with other potentially HN-inducing drugs such as diuretic drugs, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and proton pump inhibitors. Female SSNRI-users aged  ≥ 65 years concomitantly using other HN-inducing drugs were the population subgroup with the highest risk of developing HN. The identification of high-risk drug combinations and vulnerable patient subgroups represents a significant step in the improvement of drug safety and facilitates the implementation of precautionary measures.

Mechanism of gating and partial agonist action in the glycine receptor.

Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.

Pharmacotherapy of 1,044 inpatients with posttraumatic stress disorder: current status and trends in German-speaking countries.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited approved pharmacological treatment options and high symptom burden. Therefore, real-life prescription patterns may differ from guideline recommendations, especially in psychiatric inpatient settings. The European Drug Safety Program in Psychiatry ("Arzneimittelsicherheit in der Psychiatrie", AMSP) collects inpatients' prescription rates cross-sectionally twice a year in German-speaking psychiatric hospitals. For this study, the AMSP database was screened for psychiatric inpatients with a primary diagnosis of PTSD between 2001 and 2017. N = 1,044 patients with a primary diagnosis of PTSD were identified with 89.9% taking psychotropics. The average prescription rate was 2.4 (standard deviation: 1.5) psychotropics per patient with high rates of antidepressant drugs (72.0%), antipsychotics drugs (58.4%) and tranquilizing drugs (29.3%). The presence of psychiatric comorbidities was associated with higher rates of psychotropic drug use. The most often prescribed substances were quetiapine (24.1% of all patients), lorazepam (18.1%) and mirtazapine (15.0%). The use of drugs approved for PTSD was low (sertraline 11.1%; paroxetine 3.7%). Prescription rates of second-generation antipsychotic drugs increased, while the use of tranquilizing drugs declined over the years. High prescription rates and extensive use of sedative medication suggest a symptom-driven prescription (e.g., hyperarousal, insomnia) that can only be explained to a minor extent by existing comorbidities. The observed discrepancy with existing guidelines underlines the need for effective pharmacological and psychological treatment options in psychiatric inpatient settings.

A Functional K+ Channel from Tetraselmis Virus 1, a Member of the Mimiviridae.

Potassium ion (K+) channels have been observed in diverse viruses that infect eukaryotic marine and freshwater algae. However, experimental evidence for functional K+ channels among these alga-infecting viruses has thus far been restricted to members of the family Phycodnaviridae, which are large, double-stranded DNA viruses within the phylum Nucleocytoviricota. Recent sequencing projects revealed that alga-infecting members of Mimiviridae, another family within this phylum, may also contain genes encoding K+ channels. Here we examine the structural features and the functional properties of putative K+ channels from four cultivated members of Mimiviridae. While all four proteins contain variations of the conserved selectivity filter sequence of K+ channels, structural prediction algorithms suggest that only two of them have the required number and position of two transmembrane domains that are present in all K+ channels. After in vitro translation and reconstitution of the four proteins in planar lipid bilayers, we confirmed that one of them, a 79 amino acid protein from the virus Tetraselmis virus 1 (TetV-1), forms a functional ion channel with a distinct selectivity for K+ over Na+ and a sensitivity to Ba2+. Thus, virus-encoded K+ channels are not limited to Phycodnaviridae but also occur in the members of Mimiviridae. The large sequence diversity among the viral K+ channels implies multiple events of lateral gene transfer.

Severe weight gain as an adverse drug reaction of psychotropics: Data from the AMSP project between 2001 and 2016.

Severe weight gain induced by psychotropics is a known problem in psychiatry. Various drugs from different classes may lead to weight gain that may further lead to potentially life-shortening diseases, such as diabetes or cardiovascular disease. A total of 344 cases of severe weight gain (>10% of body weight) have been documented by the drug safety in psychiatry program AMSP between 2001 and 2016. Patients gained 12.7 ± 5.5 kg weight within 12±15 weeks. This equals a Body Mass Index (BMI) gain of 4.4 ± 1.9 kg/m² to a final BMI of 28.8 ± 5.5 kg/m². In addition, 142 retrospective reports documented at admission have been analyzed. Within one year these patients gained 6.4 ± 4.0 kg/m² to a final BMI of 31.9 kg/m². The weight gain was extreme in some cases. For example, 35% of the patients gained more than 20 kg. On average the patients reached overweight or even adiposity. Only 27% of the patients could loose some weight at the end of their stay. This emphasizes the relevance of this long-term problem for the patients' health. Mostly second generation antipsychotics, and therein olanzapine, as well as antidepressants and anticonvulsants have been imputed. Severe weight gain is a slow process and it is rarely documented as adverse drug reaction under real-life conditions compared to the high percentage of patients with weight gain in clinical studies. It might often remain unnoticed due to shorter stationary treatment and changing treatment settings.

The startle disease mutation α1S270T predicts shortening of glycinergic synaptic currents.

KEY POINTS: Loss-of-function mutations in proteins found at glycinergic synapses, most commonly in the α1 subunit of the glycine receptor (GlyR), cause the startle disease/hyperekplexia channelopathy in man. It was recently proposed that the receptors responsible are presynaptic homomeric GlyRs, rather than postsynaptic heteromeric GlyRs (which mediate glycinergic synaptic transmission), because heteromeric GlyRs are less affected by many startle mutations than homomers. We examined the α1 startle mutation S270T, at the extracellular end of the M2 transmembrane helix. Recombinant heteromeric GlyRs were less impaired than homomers by this mutation when we measured their response to equilibrium applications of glycine. However, currents elicited by synaptic-like millisecond applications of glycine to outside-out patches were much shorter (7- to 10-fold) in all mutant receptors, both homomeric and heteromeric. Thus, the synaptic function of heteromeric receptors is likely to be impaired by the mutation. ABSTRACT: Human startle disease is caused by mutations in glycine receptor (GlyR) subunits or in other proteins associated with glycinergic synapses. Many startle mutations are known, but it is hard to correlate the degree of impairment at molecular level with the severity of symptoms in patients. It was recently proposed that the disease is caused by disruption in the function of presynaptic homomeric GlyRs (rather than postsynaptic heteromeric GlyRs), because homomeric GlyRs are more sensitive to loss-of-function mutations than heteromers. Our patch-clamp recordings from heterologously expressed GlyRs characterised in detail the functional consequences of the α1S270T startle mutation, which is located at the extracellular end of the pore lining M2 transmembrane segment (18'). This mutation profoundly decreased the maximum single-channel open probability of homomeric GlyRs (to 0.16; cf. 0.99 for wild type) but reduced only marginally that of heteromeric GlyRs (0.96; cf. 0.99 for wild type). However, both heteromeric and homomeric mutant GlyRs became less sensitive to the neurotransmitter glycine. Responses evoked by brief, quasi-synaptic pulses of glycine onto outside-out patches were impaired in mutant receptors, as deactivation was approximately 10- and 7-fold faster for homomeric and heteromeric GlyRs, respectively. Our data suggest that the α1S270T mutation is likely to affect the opening step in GlyR activation. The faster decay of synaptic currents mediated by mutant heteromeric GlyRs is expected to reduce charge transfer at the synapse, despite the high equilibrium open probability of these mutant channels.

Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993-2015.

Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program 'Arzneimittelsicherheit in der Psychiatrie' from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for 'atypical NMS' would lead to a better understanding and, therefore, to improved treatment possibilities.

Pharmacotherapy of psychiatric inpatients with adjustment disorder: current status and changes between 2000 and 2016.

Adjustment disorder is a temporary change in behaviour or emotion as a reaction to a stress factor. Therapy consists of psychotherapy, and pharmacotherapy can be advised. However, data on the real-life pharmacological treatment are sparse. Prescription data for 4.235 psychiatric inpatients diagnosed with adjustment disorder in the time period 2000-2016 were analysed. The data were obtained from the Drug Safety Programme in Psychiatry (AMSP). Data were collected on two reference days per year; prescription patterns and changes over time were analysed. Of all patients, 81.2% received some type of psychotropic drug. Mostly antidepressants (59.8%), antipsychotics (35.5%), and tranquilisers (22.6%) were prescribed. Prescription rates for antidepressants decreased slightly over the years, while rates for antipsychotics increased, especially for atypical antipsychotics. It is important to note that the diagnosis "adjustment disorder" is most likely a working diagnosis that is used for patients in immediate need of psychiatric aid. Overall, pharmacotherapy for inpatients with this diagnosis is mostly symptom-oriented and focuses on depressive moods, agitation and anxiety. Therapy regimes changed over time and show an increased use of atypical antipsychotics with sedative properties. However, for most of the medication, there are neither evidence-based studies nor guidelines, and drugs might be contraindicated in some cases.

[Psychopharmaceutical Medication in Brandenburgian Nursing Homes - An Exploratory Study]. / Psychopharmakamedikation in brandenburgischen Pflegeheimen ­ eine explorative Studie.

OBJECTIVE: Psychopharmaceuticals are often prescribed in nursing homes for elderly. Together with the general polypharmacy, the risk for adverse drug reactions and interactions is increased. METHODS: Medication data of 398 nursing home residents were analyzed. Guided interviews and focus groups were carried out with nurses, prescribing physicians and relatives. RESULTS: About 70 % of the residents received psychotropic drugs often with sedative properties. High work load, sociodemographic development and shortage of psychiatrists and neurologists had an influence on the prescription rates. CONCLUSION: Nurses and physicians need to be aware of possible adverse drug effects and interactions of psychotropics. The overall amount of psychopharmaceuticals prescribed in nursing homes should be reduced.

Priapism induced by various psychotropics: A case series.

Objective: Priapism is a rare adverse effect of several psychotropics. Both, typical and atypical antipsychotics, as well as trazodone are known to cause priapism. The mechanism is still not fully understood, however, the most common assumption is that priapism occurs due to the α-adrenergic blocking effects of the drugs. Methods: Here we present from the AMSP database 19 cases of priapism being likely caused by a variety of psychotropics. We further reviewed case reports in order to find similarities and to identify risk factors. Results: Several patterns emerged: common was the introduction of a specific drug to a patient resulting into the immediate development of priapism, as well as a change in drug plasma concentration due to a change of drug dosage or due to comedication with certain SSRIs. Conclusion: However, priapism can occur at nearly any age and with any dose. Clinicians must be aware of the risk and reports of early signs, such as prolonged erections, should be taken seriously.

Genes for Membrane Transport Proteins: Not So Rare in Viruses.

Some viruses have genes encoding proteins with membrane transport functions. It is unknown if these types of proteins are rare or are common in viruses. In particular, the evolutionary origin of some of the viral genes is obscure, where other viral proteins have homologs in prokaryotic and eukaryotic organisms. We searched virus genomes in databases looking for transmembrane proteins with possible transport function. This effort led to the detection of 18 different types of putative membrane transport proteins indicating that they are not a rarity in viral genomes. The most abundant proteins are K⁺ channels. Their predicted structures vary between different viruses. With a few exceptions, the viral proteins differed significantly from homologs in their current hosts. In some cases the data provide evidence for a recent gene transfer between host and virus, but in other cases the evidence indicates a more complex evolutionary history.

Identification of Intrahelical Bifurcated H-Bonds as a New Type of Gate in K+ Channels.

Gating of ion channels is based on structural transitions between open and closed states. To uncover the chemical basis of individual gates, we performed a comparative experimental and computational analysis between two K+ channels, KcvS and KcvNTS. These small viral encoded K+ channel proteins, with a monomer size of only 82 amino acids, resemble the pore module of all complex K+ channels in terms of structure and function. Even though both proteins share about 90% amino acid sequence identity, they exhibit different open probabilities with ca. 90% in KcvNTS and 40% in KcvS. Single channel analysis, mutational studies and molecular dynamics simulations show that the difference in open probability is caused by one long closed state in KcvS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phes in the cavity of the channel, which blocks ion flux. The frequent occurrence of Ser or Thr based helical kinks in membrane proteins suggests that a similar mechanism could also occur in the gating of other ion channels.

The Startle Disease Mutation E103K Impairs Activation of Human Homomeric α1 Glycine Receptors by Disrupting an Intersubunit Salt Bridge across the Agonist Binding Site.

Glycine receptors (GlyR) belong to the pentameric ligand-gated ion channel (pLGIC) superfamily and mediate fast inhibitory transmission in the vertebrate CNS. Disruption of glycinergic transmission by inherited mutations produces startle disease in man. Many startle mutations are in GlyRs and provide useful clues to the function of the channel domains. E103K is one of few startle mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface. Homology modeling shows that the side chain of Glu-103 is close to that of Arg-131, in loop E of the complementary side of the binding site, and may form a salt bridge at the back of the binding site, constraining its size. We investigated this hypothesis in recombinant human α1 GlyR by site-directed mutagenesis and functional measurements of agonist efficacy and potency by whole cell patch clamp and single channel recording. Despite its position near the binding site, E103K causes hyperekplexia by impairing the efficacy of glycine, its ability to gate the channel once bound, which is very high in wild type GlyR. Mutating Glu-103 and Arg-131 caused various degrees of loss-of-function in the action of glycine, whereas mutations in Arg-131 enhanced the efficacy of the slightly bigger partial agonist sarcosine (N-methylglycine). The effects of the single charge-swapping mutations of these two residues were largely rescued in the double mutant, supporting the possibility that they interact via a salt bridge that normally constrains the efficacy of larger agonist molecules.

Ion Channel Activity of Vpu Proteins Is Conserved throughout Evolution of HIV-1 and SIV.

The human immunodeficiency virus type 1 (HIV-1) protein Vpu is encoded exclusively by HIV-1 and related simian immunodeficiency viruses (SIVs). The transmembrane domain of the protein has dual functions: it counteracts the human restriction factor tetherin and forms a cation channel. Since these two functions are causally unrelated it remains unclear whether the channel activity has any relevance for viral release and replication. Here we examine structure and function correlates of different Vpu homologs from HIV-1 and SIV to understand if ion channel activity is an evolutionary conserved property of Vpu proteins. An electrophysiological testing of Vpus from different HIV-1 groups (N and P) and SIVs from chimpanzees (SIVcpz), and greater spot-nosed monkeys (SIVgsn) showed that they all generate channel activity in HEK293T cells. This implies a robust and evolutionary conserved channel activity and suggests that cation conductance may also have a conserved functional significance.

Large dsDNA chloroviruses encode diverse membrane transport proteins.

Many large DNA viruses that infect certain isolates of chlorella-like green algae (chloroviruses) are unusual because they often encode a diverse set of membrane transport proteins, including functional K(+) channels and aquaglyceroporins as well as K(+) transporters and calcium transporting ATPases. Some chloroviruses also encode putative ligand-gated-like channel proteins. No one protein is present in all of the chloroviruses that have been sequenced, but the K(+) channel is the most common as only two chloroviruses have been isolated that lack this complete protein. This review describes the properties of these membrane-transporting proteins and suggests possible physiological functions and evolutionary histories for some of them.

Agonist and antagonist binding in human glycine receptors.

The human glycine receptor (hGlyR) is an anion-permeable ligand-gated channel that is part of a larger superfamily of receptors called the Cys-loop family. hGlyRs are particularly amenable to single-channel recordings, thus making them a model experimental system for understanding the Cys-loop receptor family in general. Understanding the relationship between agonist binding and efficacy in Cys-loop receptors should improve our future prospects for making specific agonists or antagonists. However, at present, there is no high-resolution structure for the complete hGlyR, and thus, modeling is needed to provide a physical framework on which to interpret single-channel data. The structure of the glutamate-gated chloride channel from Caenorhabditis elegans shows a much higher level of sequence identity to human hGlyR than previous templates such as AChBP or the bacterial channels, GLIC and ELIC. Thus, we constructed a model of the hGlyR and validated it against previously reported mutagenesis data. We used molecular dynamics to refine the model and to explore binding of both an agonist (glycine) and an antagonist (strychnine). The model shows excellent agreement with previous data but also suggests some unique features: (i) a water molecule that forms part of the binding site and allows us to account for some previous results that were difficult to reconcile, (ii) an interaction of the glycine agonist with S129, and (iii) an effect from E211, both of which we confirmed with new site-directed mutagenesis and patch clamp recordings. Finally, examination of the simulations suggests that strychnine binding induces movement to a conformational state distinct from the glycine-bound or apo state, not only within the ligand-binding domain but also in the transmembrane domain.