KCNMA1

By investigating a molecule in the brain tied to cellular communication, scientists uncover important information about the proteins that do -- and do not -- influence alcohol drinking behavior. Ethanol -- the compound found in alcoholic beverages -- interferes with the normal functioning of a long list of biological molecules, but how each of these interactions contributes to the behavioral effects of alcohol is not fully understood. A guiding, but elusive, goal of researchers is to identify the protein (or proteins) to which ethanol binds that makes some people vulnerable to excessive drinking. Solving this question would point the way to effective therapies for alcohol use disorder, which affects more than 10% of the U.S. adult population and is responsible for a myriad of health and societal issues. Previous studies identified one such molecule, a protein widely expressed in the brain, called the BK channel. Ethanol can directly interact with a component of BK channels, known as the α subunit, to facilitate their opening. However, scientists at Scripps Research found that this interaction may not drive behaviors related to alcohol abuse as much as previously thought. Their study, appearing in the journal Molecular Psychiatry on December 22, 2023, demonstrates that preventing ethanol from interacting with the BK α subunit does not reduce or increase the motivation to consume alcohol in mice. The relationship between the BK α subunit and ethanol had previously been explored in vitro, ex vivo and in live invertebrates. Previous studies suggested that the BK α subunit was involved in an animal's response to alcohol exposure, but there was a gap in understanding its role in mammals, particularly for the control of alcohol drinking. "Knowing what a molecule does from in vitro experiments really doesn't tell you much about what the behavioral consequences of that action might be," says senior author Candice Contet, PhD, associate professor in the Department of Molecular Medicine at Scripps Research. "Things get complicated in vivo, because there are many layers of modulation that may occur in a cell-type specific manner. Moreover, the initial effect often changes with repeated or prolonged exposure to alcohol. We thus sought to determine whether the ability of ethanol to alter BK channel activity was in any way influencing the motivation to drink alcohol." Tackling this question didn't lend itself well to conventional pharmacological testing: blocking BK channels with a drug causes tremors, which then interfere with drinking behavior. However, Contet's collaborator Alex Dopico, MD, PhD, of the University of Tennessee, had identified a residue in the mouse BK α subunit that is required for ethanol to activate BK channels but is dispensable for normal BK channel activity, as shown in frog eggs. In the new study, Contet and her colleagues leveraged this discovery to unlock the significance of ethanol's interaction with BK channels for alcohol drinking in mice. Accordingly, the team tested mice that had a mutation in this particular BK α subunit residue. First, they found that the mutation prevented alcohol from altering the firing properties of neurons in the medial habenula, a brain region with high levels of BK channels, thereby demonstrating that it also confers resistance to ethanol in mouse brain cells, not just in frog eggs. At the behavioral level, the mice harboring the mutation did not display any anomalies when compared to control littermates. Notably, they exhibited the standard signs of intoxication upon alcohol injection, such as loss of balance and hypothermia, and they consumed the same amount of alcohol when tested under various conditions of moderate or excessive drinking. "The lack of effect of the mutation was surprising, especially in light of our previous results showing that other BK channel subunits, β1 and β4, influence alcohol intake escalation in the same model of alcohol dependence," says Contet. "However, these negative results, which were replicated in multiple cohorts and both sexes, are just as important as positive ones, because they encourage the field to study other targets rather than focusing on the wrong culprit." While the study does not point to a critical role of the BK α subunit in the motivation to drink alcohol or several physiological responses related to ethanol intoxication and withdrawal, the group will continue to explore whether the molecular target plays a role in other aspects of alcohol use disorder. "Ethanol is highly pleiotropic. Beyond its reinforcing effects, it alters the functioning of multiple organs and cell types," Contet says. "It is likely that ethanol's interaction with BK channels contribute to some of these effects, but we've only explored the tip of the iceberg so far; the next challenge will be to find the right experimental readout." This work was supported by funding from the National Institutes of Health (AA020913, AA006420, AA026685, AA027636, AA027372, AA020889, AA010422, AA021491, AA013498, AA011560, AA007456)

STAMFORD, Conn., Feb. 16, 2023 (GLOBE NEWSWIRE) -- GeneDx Holdings Corp. (GeneDx) (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, continues to demonstrate how the study of rare disease can improve understanding of the biology of common disorders. Research published in the October 2022 issue of Nature Genetics, to which GeneDx contributed data and authorship, yields insights into the role of two-pore-domain potassium channels (K2P) in rare disease and explores the role genes might play in the newly described developmental delay with sleep apnea (DDSA). Such connections better enable the exploration of pharmacological solutions to common diseases impacting wide swaths of the general population. Sleep apnea, characterized by abnormal, interrupted breathing during sleep, is a common disorder that represents a global public health burden thought to affect up to one in five people worldwide and approximately 30 million Americans. Poor sleep quality often results in decreased quality of life and increased risk of comorbidities, such as cardiovascular disease, diabetes and depression. The study describes DDSA, a newly identified condition caused by de novo gain-of function variants clustering in the X-gate motif of the TASK-1 channel encoded by KCNK3. TASK-1 is a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Functional studies indicate that TASK channel inhibitors may be effective at inhibiting abnormal channel activity caused by these variants, illuminating the underlying biology of sleep apnea and pointing to possible therapeutic options for patients with DDSA and common sleep apnea. “These findings indicate how research into rare disease can uncover findings that are potentially applicable to much broader segments of the general population and also represent important progress for the pharmacological management of sleep apnea,” said Dr. Paul Kruszka, Chief Medical Officer of GeneDx. “Sleep apnea’s high prevalence and the imperfection of existing therapies mean there is sizeable appetite for developing new treatment approaches.” Through its robust rare disease data set, GeneDx is working to advance drug discovery and development, and accelerate research to help identify therapeutic targets for common diseases. With the deep genomic information available from GeneDx’s exome and genome testing, combined with its clinical insights, the company is able to help connect biopharmaceutical companies with patients to improve clinical trial enrollments and recruitment and improve patient outcomes by connecting them to therapies. About GeneDx (formerly Sema4) GeneDx delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the world’s largest rare disease data sets. For more information, please visit genedx.com and connect with us on LinkedIn, Facebook, and Instagram. Media contact Stephanie Kahan Press@genedx.com Investor contact Tricia Truehart Investors@genedx.com

Researchers have unlocked one of the secrets as to why some forms of Strep A are associated with severe invasive infection. Griffith University researchers have unlocked one of the secrets as to why some forms of Strep A are associated with severe invasive infection. Invasive Strep A diseases are responsible for more than 163,000 deaths each year globally and a recent increase in cases of invasive Strep A disease has been observed in Victoria, New South Wales and internationally. For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body. "The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally," Associate Professor Pandey said. "The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study. "SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection." Professor Good said: "We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence." "Essentially, the less SLO present, the less severe the case of Strep A." SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent. This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis. This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs. Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University's Institute for Glycomics and which is now in a clinical trial. The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.