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We study how ion channels regulate information coding in dynamic systems. In my lab, we combine the genetic manipulation of ion channels with electrophysiology and in vivo brain and muscle physiology. Our goal is to understand the ion channel biophysics behind neuromuscular function in animal models and humans.
BK Channels (KCNMA1)
Our lab studies focus on the BK (Big K+) 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 are the ‘King of Ion Channels’ based on several exceptional features, including their unusually large unitary conductance, allosteric voltage and Ca2+-dependent gating, and well-characterized biophysical properties. We created a variety of transgenic lines (Kcnma1N999S, Kcnma1D434G, Kcnma1H444Q, Kcnma1–/–, Tg-BKR207Q, and Kcnma1flox-tdTomato) to study BK channel function and pathophysiology, in systems ranging from circadian rhythm to cardiac rhythm, and motor function, urodynamics, reproductive function, neurovascular coupling, hearing, and human (KCNMA1 channelopathy) and animal (Ryegrass Staggers) neurological disease.
KCNMA1-linked channelopathy is a rare new neurological disorder with less than 70 documented cases at present. 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 goal is to understand how clinical symptoms are produced by the changes in BK channel activity associated with patient mutations. Patients and families can find out more about KCNMA1-linked channelopathy here.
- CRISPR gene-editing produces first mouse model allelic series for KCNMA1 channelopathy patient variants
🐁 The KCNMA1 International Advocacy Foundation (KCIAF) is founded for patients with KCNMA1-linked disorders
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.
🐁 University of Maryland School of Medicine Research Illuminates Key Aspects of How We Fall Asleep and Wake Up
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 had been mostly discounted based on the weak relative expression. We discovered 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.
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. BK channels have been extensively studied at the biophysical level, and our studies build on this work by discovering the impact of tissue-specific variation in BK current properties a specialized dynamic system, the circadian clock. 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 channel biophysical properties and neuronal and circuit excitability can be established.
Novel Roles for BK Channels
BK channels are widely, but specifically, expressed in both excitable (brain and muscle) and non-excitable tissues (kidney and bone). 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. We made several transgenic mouse lines (Kcnma1–/–, Tg-BKR207Q, and Kcnma1flox-tdTomato) for studies that will identify new systems in which BK channels play dominant roles.
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 created 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, we developed novel methodology for simultaneous optical imaging of multiple quantitative FRET biosensors within single neurons and circuits. We used these new FRET sensors to track the rhythmic fluctuations in membrane and intracellular signaling.
The lab is supported by grants from The National Heart, Lung, and Blood Institute, The Brain Initiative, 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 Research (The American Physiological Society). Interested in supporting our research directly? Click here.