Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation.

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

Molecular Pharmacology of K2P Potassium Channels.

Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K2P channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K2P channel blockers and activators.

Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey.

BACKGROUND: As their long-term prognosis improves, women with CF are increasingly choosing to have children, but the safety of CFTR modulators in pregnancy and breastfeeding is currently unknown. METHODS: A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation. RESULTS: We identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding. CONCLUSIONS: CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects.

Scorpion venomics: a 2019 overview.

Introduction: A few scorpions are dangerous to humans. Their medical relevance was the initial driving force for venom research. By classical biochemistry and molecular cloning, several venom peptides and their coding transcripts were characterized, mainly those related to toxins. The discovery of other components with novel activities and potential applications has revitalized the interest in the field in the last decade and a half. Nontoxic scorpion species have also attracted major interest.Areas covered: Advances in the identification of scorpion venom components via high-throughput venomics (genomics, transcriptomics and proteomics) up to 2019 are summarized. A classification system for venom-related transcripts and proteins, together with an intuitive systematic nomenclature for RNAseq-generated transcripts are proposed. Venom components classified as Na+, K+, Ca2+, Cl- and TRP channel toxins, enzymes, protease inhibitors, host defense peptides and other peptidic molecules are briefly reviewed, giving a comprehensive picture of the venom.Expert opinion: Modern high-throughput technologies applied to scorpion venom studies have resulted in a dramatic increase in both, the number and diversity of available sequences, leading to a deeper understanding of the composition of scorpion venoms. Still, many newly-discovered venom constituents remain to be characterized, to complete the puzzle of scorpion venoms.

R560S: A class II CFTR mutation that is not rescued by current modulators.

BACKGROUND: New therapies modulating defective CFTR have started to hit the clinic and others are in trial or under development. The endeavour of drug discovery for CFTR protein rescue is however difficult one since over 2000 mutations have been reported. For most of these, especially the rare ones, the associated defects, the respective functional class and their responsiveness to available modulators are still unknown. Our aim here was to characterize the rare R560S mutation using patient-derived materials (rectal biopsies and intestinal organoids) from one CF individual homozygous for this mutation, in parallel with cellular models expressing R560S-CFTR and to assess the functional and biochemical responses to CFTR modulators. METHODS: Intestinal organoids were prepared from rectal biopsies and analysed by RT-PCR (to assess CFTR mRNA), by Western blot (to assess CFTR protein) and by forskolin-induced swelling (FIS) assay. A novel cell line expressing R560S-CFTR was generated by stably transducing the CFBE parental cell line and used to assess R560S-CFTR processing and function. Both intestinal organoids and the cellular model were used to assess efficacy of CFTR modulators in rescuing this mutation. RESULTS: Our results show that: R560S does not affect CFTR mRNA splicing; R560S affects CFTR protein processing, totally abrogating the production of its mature form; R560S-CFTR evidences no function as a Cl- channel; and none of the modulators tested rescued R560S-CFTR processing or function. CONCLUSION: Altogether, these results indicate that R560S is a class II mutation. However, unlike F508del, it cannot be rescued by any of the CFTR modulators tested.

Modernized Classification of Cardiac Antiarrhythmic Drugs.

BACKGROUND: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. METHODS: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. RESULTS: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. CONCLUSIONS: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

Pharmacological therapy for atrial fibrillation: current options and new agents.

Atrial fibrillation is the most commonly encountered cardiac arrhythmia and is directly or indirectly responsible for considerable mortality, morbidity and health care burden. The available medical therapy is limited by marginal efficacy, end-organ toxicity, as well as the potential for undesired ventricular proarrhythmia. Elucidation of the potential mechanisms that underlie the development of atrial fibrillation may provide new targets for drugs that circumvent the problems associated with current medical options. This review focuses on the current and potential future pharmacological agents directed at rhythm control and maintenance of sinus rhythm.