Ion Channel Regulation: Molecules to Disease

The “Ion Channel Regulation Conference: Molecules to Disease” conference was held in Lisbon, Portugal, July 7–12, 2019 at the Lisbon Marriott Hotel. The conference focused on the latest research on mechanisms of ion channel regulation, its impact on the physiology of diverse cell types, and the potential for targeting ion channel regulation in drug development. Accounting for ~1–2% of genes in the human genome, ion channels control many essential cellular and physiological processes including; neuronal firing and synaptic transmission, muscle contraction, hormonal secretion, fluid homeostasis, gastric acidification, and gene expression. Inherited or de novo mutations in ion channels (the so-called ‘channelopathies’) underlie devastating human diseases such as; epilepsy, autism, chronic pain, cystic fibrosis, diabetes, and lethal cardiac arrhythmias. Not surprisingly, ion channels not only represent important targets for existing therapeutics, but also hold vast untapped potential for future drug development efforts. This FASEB SRC plays a vital role in fueling the engine of discovery in this vital research area by bringing together, in a concentrated, intense week, leading investigators from diverse fields to share the latest and most exciting developments in Ion Channel Regulation, with the aim of sharing information across disciplines, establishing new personal contacts, and promoting future collaborations. This conference has taken place every other year since its inception in 2003 and was arguably the most important meeting in the ion channel field in 2019. It serves as an essential forum for leading scientists from the US, Canada, Europe, Asia and other parts of the globe to present and discuss their latest and most important research. Over the four and a half days of the meeting, there were 32 full-length talks, 2 keynote lectures, 21 short talks chosen from submitted abstracts, and 66 poster presentations. Impressively, there was full participation by all attendees as everyone at the conference either presented a talk, participated as a discussion leader, a panelist, or presented a poster.

The meeting brought together 122 researchers (57% men and 43% women) from academia (105), government (6), and industry (11) at diverse career stages, including senior and mid-career faculty/investigators (46), junior faculty/investigators (23), staff scientists (8), postdoctoral trainees (14), graduate students (27), and others (4). The attendees hailed from the USA and 14 other countries, including Australia, Austria, Canada, Chile, China, France, Finland, Germany, Great Britain, Hungary, India, Israel, Italy, Japan, Mexico, Singapore, Switzerland, and Thailand. The thematic sessions were: 1) Ion Channelopathies, 2) Ion Channel Modulation, 3) Ion Channel Structure and Function, 4) Organelle Ion Channels, 5) Ion Channel Engineering, 6) Ion Channel Neurophysiology, 7) Cardiovascular Ion Channels, 8) Ion Channels and Pain, and 9) Ion Channel Rhythms. 20 of the 54 (37%) speakers, 4 of the 9 session chairs (44%), and 1 of the 2 keynote speakers (50%) were women.

Before recapping the scientific details of the topics presented at this most recent meeting, we will delve into the history of this meeting to provide some context. This FASEB SRC was started in 2003 to provide a forum to present and discuss the latest research findings on the topic of Ion Channel Regulation, with the premise that this would serve to fuel the “engine of discovery” necessary to advance basic knowledge about ion channels structure and function, their roles in disease, and translation into innovative therapies. The conference achieves this by bringing together basic and clinical scientists from academia and industry from different disciplines but with a common interest in ion channel regulation. By including trainees and new investigators as speakers and programming of numerous career development activities, the conference also aims to nurture the next generation of ion channel biologists, particularly women and under-represented minorities (URMs) in science. The conference has been held 8 previous times and has been very successful in accomplishing the broad objectives and consistently recruiting new attendees that bring fresh ideas to the field.

The conference opened with a session on Ion Channelopathies which began with a talk from Ivy Dick (University of Maryland) on the impact of different Timothy syndrome mutations on distinct inactivation mechanisms in L-type calcium channels and a lower susceptibility of mutant channels to inhibition by pharmacological blockers. The session was capped by a keynote lecture by Dr. Frances Ashcroft (Ph.D., Sc.D., FRS, Royal Society GlaxoSmithKline Research Professor at the University Laboratory of Physiology, Oxford and a Fellow of Trinity College, Oxford.) who discussed the role of impaired ion channel regulation of insulin secretion in diabetes. Her research centers on how changes in blood glucose levels regulate insulin secretion from the pancreatic beta-cell and how this process is impaired in diabetes. She discovered that the ATP-sensitive potassium (K_ATP) channel serves as the molecular link between glucose elevation and insulin secretion. Mutations in K_ATP channel genes cause a rare inherited form of diabetes (neonatal diabetes), and her work with Professor Hattersley has enabled patients with this disorder to switch from insulin injections to drug therapy (1). Her current focus is on beta-cell metabolism and how this is affected and contributes to pathogenesis of type 2 diabetes.

On the second day, Steven Marx (Columbia University), in a tour-de-force of perseverance, discussed his laboratory’s efforts to decipher how exactly β-adrenergic agonists increase Ca²⁺ influx via Ca_V1.2 calcium channels in cardiomyocytes during “fight or flight”. The answer, as per Steven is that “it’s all about the neighborhood”: transgenic expression of mutant α1C (Ca_V1.2) subunits lacking capacity to bind CaVβ can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling (2). However, these β-less Ca²⁺ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts.

Dr. Daniel L. Minor (Professor, Cardiovascular Research Institute, Departments of Biochemistry & Biophysics, and Cellular & Molecular Pharmacology, University of California, San Francisco USA) explained to the audience how his laboratory was using functional, chemical, and structural approaches to develop new chemical means to target members of the thermo- and mechano-sensitive TREK subfamily of two-pore domain (K_2P) potassium channels (3).

On day three, Dr. Joe Mindell (NINDS) talked, not about ion channels, but about the chloride transporter ClC-7. In an elegant example of the promise of the bench to bedside approach espoused by the NIH, Joe demonstrated how mutations in ClC-7 (4) – which is normally directed to the lysosomes, exhibits a classical 2Cl^-/1H⁺ stoichiometry and is inhibited under low extracellular pH – result in osteopetrosis, a disease characterized by increased bone radiodensity because of ineffective osteoclast-mediated bone resorption. Remarkably, in several patients, normalizing the pH corrected the disease.

The marriage of ion channel function and bioengineering was showcased by several talks in the Ion Channel Engineering session including one by Dr. Anna Moroni (University of Milan - Milano, Italy) who showed that the nucleotide gating domain of the human hyperpolarization-activated cyclic nucleotide gated channel 1 (HCNl) integrates ligand and voltage gating by bridging the transmembrane voltage sensor domain with the cytosolic C-linker via hydrophobic and hydrophilic interactions (5). Posters from her group in collaboration with the group of Dr. Gerhard Thiel (TU Darmstadt, Plant Membrane Biophysics) described a split transcription factor system to induce transcription of a small K⁺ channel by blue light.

The importance of ion channels in neurophysiology and cardiovascular function was presented in great detail on the fourth day of the conference. Dr. Anjali Rajadhyaksha (Weill Cornell Medicine, Cornell University, NY) talked about how L-type channels conduct signals to facilitate activity-dependent-gene transcription and long-term potentiation and how this relates to cocaine addiction. Her talk concluded that a tripartite complex of dopamine D1 receptors, Cav1.2 channels and glutamate AMPARs are key for drug-associated contextual memories (6). Dr. Isabelle Deschenes (Case Western Reserve University, Ohio) presented evidence that voltage-gated sodium channels assemble and gate as dimers using the case of the cardiac NaV1.5 channel, highlighting the possibility that biophysical coupling of Nav1.5 may be a potential target for future channelopathy therapies (7).

The last day began with a charged session on Ion Channels and Pain, with first-time attendee Dr. May Khanna (University of Arizona), telling the tale of how indirectly targeting the Nav1.7 voltage-gated sodium channel may finally unlock this channel’s undeniable pain potential. Following on from a brilliant primer on the multiple contributions of Nav1.7 to pain pathways by Dr. John Wood (University College London, London, Great Britain)(8), May presented evidence on how preventing the post-translational modification of a cytosolic protein that controls Nav1.7 function (9, 10) could be leveraged to develop small molecules to curb neuropathic pain.

The meeting ended with the second keynote address, given by Dr. Bruce Bean (Professor, Department of Neurobiology, Harvard Medical School, Boston, MA), who in a talk titled “Channels in Concert” posed the question of how particular combinations of ion channels interact to produce the variety of firing patterns seen in different kinds of neurons (11, 12). By “deconstructing” experimental data from patch clamp recordings, he concluded that very small currents can powerfully influence spiking patterns and that contextual relevance of the channels can shape the neuron’s firing patterns. These lessons about control of firing in normally functioning neurons are key to understanding pathophysiology in disease states, including epilepsy, neuropathic pain, amyotrophic lateral sclerosis, and Parkinson’s Disease.

A special thanks to Dr. Elena Oancea (Brown University) for moderating the “Meet the Experts: Career Panel- from Academia and Industry” where panelists Andrea Brüggemann, Jean-Ju Chung, Mark Dell’Acqua, Mario Delmar, and Isabelle Deschenes answered questions ranging from work-life balance, when to apply for a position, industry vs. academia and navigating between both, mentorship/mentee relationships etc.

Thanks also to Dr. Shai Silberberg (Director for Research Quality, NINDS) presented the second of the career development sessions titled “Navigating the growing emphasis on rigor and transparency by journals, funders, and the universities”. Shai has been leading NIH’s efforts to increase the excellence of science and the completeness of research reporting.

Results from the feedback evaluation conveyed a feeling of overall good organization of the meeting and interesting topics. More than 80% of all respondents had favorable comments regarding the general sessions, poster sessions, and scientific content and indicated that they plan to attend this meeting in the next 2 to 3 years and that they would recommend attending this meeting to other researchers.

Figure 1:

Selfie of attendees with co-organizers Henry Colecraft and Rajesh Khanna

Figure 2:

Caption: Poster presentation winners (right to left): 1^st place - Scott A. Kanner; 2^nd place - Nadine J. Ortner; 3^rd place - Nicholas C. Vierra.