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The KCNMA1 International Advocacy Foundation (KCIAF) is founded for patients with KCNMA1-linked channelopathy
University of Maryland School of Medicine Research Illuminates Key Aspects of How We Fall Asleep and Wake Up
My lab studies how ion channels regulate membrane excitability and information coding in the brain and in muscles. In my lab, we combine the genetic manipulation of ion channels with electrophysiology and in vivo physiology. Our goal is to understand how variation in the biophysical properties of ion channels, such as from genetic mutations, controls brain function and physiology in animal models and humans.
BK Channels (KCa1.1)
Our current studies focus on a unique potassium channel, BK (Big K+), the large conductance voltage and Ca2+-activated K+ channel. The BK channel pore-forming alpha subunit is encoded by a single gene (KCNMA1 in humans, or Slo/Slowpoke in mouse and flies, respectively). Like other Kv family members, BK channels are comprised of a tetramer of alpha subunits, modulatory beta (β1-4) and gamma subunits (ɣ1-4 or LRRC26, 52, 55, and 38), and are closely localized with intracellular Ca2+ sources such as voltage-gated Ca2+ channels and RyRs.
BK channels serve as an excellent substrate for linking ion channel properties to intracellular signaling due to several exceptional features, including their unusually large unitary conductance, allosteric voltage and Ca2+-dependent gating, and well-characterized biophysical properties. Several years ago, I made a deletion of the gene encoding the BK channel in mouse (Kcnma1–/– or Slo–/–). We and our collaborators showed that BK channels regulate brain (circadian rhythms, neurovascular coupling, and aspects of hearing), locomotor, heart , bladder, and reproductive function, and are the targets of a fungal neurotoxin that causes Ryegrass Staggers (a neuronal and muscle ataxia disorder of livestock).
In people, mutations in KCNMA1, the gene that encodes the pore-forming subunit of the BK channel, have been linked to seizures, paroxysmal dyskinesia, and other types of neuromuscular and neurological dysfunction. We are studying how human genetic variation (pathological mutations and single nucleotide polymorphisms) influence neuronal firing patterns and brain and motor function. Our first priority is to understand how clinical symptoms are produced by the changes in BK channel activity associated with patient mutations. Find out more about this new, very rare KCNMA1-linked channelopathy here.
Suprachiasmatic Nucleus (SCN)
Circadian physiology is an ideal model system for studying information coding. Daily behavioral and physiological rhythms (~ 24 hrs) are a universal trait of animals, vital for adaptation to their environment and overall fitness. In mammals, lesion and transplantation studies have localized the principal circadian pacemaker to the suprachiasmatic nucleus (SCN) of the hypothalamus, identifying a discrete neural substrate for a complex behavior. We identified a novel role for the BK channel in the daily patterning of neural activity in the SCN. Kcnma1–/– mice have degraded circadian behavioral and physiological rhythms, and their SCN neurons exhibit aberrant daily action potential rhythms in the SCN circuit.
We are currently studying the circadian regulation of BK current properties in SCN neurons and how specific properties of the BK current influence the neural representation of circadian time.
BK Channels in Cardiovascular Function
BK channels are directly implicated in cardiovascular function through their regulation of vascular tone. However, a role for BK channels in the heart itself has been mostly discounted based on the weak relative expression. We recently found that several selective blockers of BK channels caused a counter-intuitive decrease in heart rate (bradycardia). BK antagonist-induced bradycardia was not observed in mice lacking BK channels (Kcnma1–/–), supporting a role for the channels in controlling heart rate and the confirming specificity of this effect. The aims of this project are to determine the mechanism and integrated contribution of BK channels in the vasculature, neurons, and the heart itself to cardiovascular function.[/expand]
Alternate Splicing of Kcnma1
BK channels are physiologically activated by voltage and Ca2+, modulating a diversity of membrane signals in different cells types. Even in excitable cells, such as neurons and muscle where they play prominent roles, their influence encompasses diverse roles in action potential repolarization, afterhyperpolarizations, repetitive firing, spontaneous firing, neurotransmitter release, plateau potentials, and baseline membrane potentials. Although BK channels have been extensively studied at the biophysical level, the impact of tissue-specific variation in BK current properties has only been addressed in a few specialized systems, such as the non-mammalian cochlea.
By combining genetic manipulation of BK channels and cloning of native splice variants with cellular, circuit, and physiological recordings, we are identifying novel systems, such as the suprachiasmatic nucleus, where direct links between BK properties and excitability can be established.
Novel Roles for BK Channels
BK channels are widely, but specifically, expressed in both excitable and non-excitable tissues. Overall, less is known about their roles in non-excitable cell types or intact physiological systems. Unlike the voltage-gated K+ channel family, there is only one gene that encodes the BK channel, and Kcnma1–/– mice display a surprising number of phenotypes at the cellular and systems levels. This lack of redundancy has enabled us to use the BK channel deletion mouse as a selective mechanism for perturbing signaling in a variety of pathways. To identify new systems in which BK channels play dominant roles, we are conducting phenotypic screens in Kcnma1–/– mice with global and tissue-specific conditional deletions of the BK channel.
Imaging Circadian Rhythms in Intracellular Signaling in the Brain’s Clock Circuit
To understand how the time-of-day code is communicated from the brain’s clock to the body, we are developing new Brain Initiative-funded tools to track circadian rhythms in neural activity and intracellular signaling. Measuring the temporal and spatial dynamics across key signaling pathways requires coordinated observation of multiple networks within individual cells and multiple neurons within intact circuits. In collaboration with Megan Rizzo and Tom Blanpied at UMB SOM, we are developing novel methodology for simultaneous optical imaging of multiple quantitative FRET biosensors within single neurons and circuits (Brain Initiative-Funded). My lab is working to validate the limits of temporal resolution, using these new FRET sensors to track the rhythmic fluctuations in membrane and intracellular signaling. These studies will provide an unprecedented window into the activity levels and phase relationships for intracellular circadian signaling hubs.
The lab is supported by grants from The National Heart, Lung, and Blood Institute, The National Institute of Diabetes and Digestive and Kidney Diseases, The National Science Foundation, The American Heart Association, and The S&R Foundation Ryuji Ueno Award for Ion Channels or Barrier Function Research (The American Physiological Society). Interested in supporting our research directly? Click here.