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CVRI Scientists
Ion channels and arrhythmias
Lily Y. Jan, Ph.D.
Professor of Physiology and Biochemistry & Biophysics; Investigator, Howard Hughes Medical Institute; Jack and DeLoris Lange Endowed Chair of Physiology and Biophysics
Research Interests:
Studies of potassium channels
Summary:
Potassium channels are widely distributed. In the brain, potassium channels regulate neuronal signaling. Potassium channels may also regulate cell volume and the flow of salt across epithelia, control heart rate, vascular tone, the release of hormones such as insulin, and protect neurons and muscles under metabolic stress.
How can potassium channels serve so many different physiological functions? Potassium channels come in many different flavors; they differ in how their activities are regulated as well as the exact manner they allow passage of potassium ions. Many different potassium channels often co-exist in a cell. This richness in potassium channel variety was one of the factors that stemmed early attempts for biochemical purification of potassium channels.
How does a potassium channel allow potassium ions but not the smaller sodium ions to go through? How does a potassium channel alter its activity in response to electrical and chemical signals? How do potassium channels contribute to signaling and plasticity in the brain? How does a cell control the number and type of potassium channels in its subcellular compartments? How might potassium channels have arisen during evolution? We have been fascinated with these questions, and believe what potassium channels will teach us may also be of relevance to other membrane proteins.
To study potassium channels, we have chosen a molecular approach that isolates individual potassium channel genes so that the channels they give rise to can be studied one at a time and then compared with potassium channels in native tissues. This molecular study was initiated by positional cloning of the Shaker voltage-gated potassium (Kv) channel gene in the fruit fly and expression cloning of mammalian inwardly rectifying potassium (Kir) channels, founding members of two large, distantly related families of potassium channels in organisms ranging from bacteria to man.
Potassium channel mutations cause diseases of the brain (epilepsy, episodic ataxia), ear (deafness), heart (arrhythmia), muscle (myokymia, periodic paralysis), kidney (hypertension), pancreas (hyperinsulinemic hypoglycemia, neonatal diabetes), and developmental abnormalities of neural crest-derived tissues (Andersen's syndrome). Conversely, the KCNK9 potassium channel gene acts as a dominant oncogene and is amplified or otherwise over-expressed in several types of human carcinomas. Underscoring potassium channels' critical physiological functions, potassium channel openers and blockers have been developed for pharmaceutical purposes. A better understanding of potassium channel function will not only satisfy our curiosity, but will have clinical significance.
How do we study potassium channels? One unique advantage in channel studies is the possibility to examine one channel at a time, with sub-millisecond resolution, for many seconds, in experimentally determined intracellular and extracellular environments. In addition to biophysical, biochemical, and cell biological studies of channel assembly, trafficking, regulation and function, we need to learn how potassium channels are targeted to specific subcellular compartments of neurons in the mammalian brain, how they respond dynamically to neuronal activity and in turn modulate neuronal signaling. To understand how potassium channels work, it will be necessary to explore advances in genomics as well as genetics, and incorporate any useful methodologies suited for membrane proteins.
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Takashi Mikawa, Ph.D.
Professor of Anatomy, Camilla and George D. Smith Distinguished Professorship in Science and Medicine
Research Interests:
Morphogenesis; developmental regulation of organogenesis
Summary:
Our group investigates the molecular mechanisms involved in the differentiation and patterning of the cardiovascular and central nervous systems. Both organ systems share a common developmental plan to establish their extremely complicated structures and functions: i) construction of a tubular structure from an epithelial sheet along midline body axis, ii) subdivision of the epithelial tube into zones for distinct functional components of the organ, iii) proliferation of cells along a perpendicular axis to the epithelial sheet (clone unit), and iv) cell fate diversification within clone units. Thus, growth of both organs is characterized by the daughter cells from the epithelial sheets proliferating vertically while remaining in close association, thereby generating clone arrays. Three dimensional spherical structures of both the heart and brain are established by the lateral packing of clone units. These findings indicate that each clone is a primary unit for both differentiation and morphogenesis of these organ systems. We are currently analyzing the molecular basis of several of these processes including a) formation of a tubular organ primordium; establishment of the midline identity along which a tubular primordium forms; b) subdivision of neural and non-neural zones during development of the retina (an extension of neural tube); and c) diversification within clone units into the glial and neuronal cell fate (neural retina, optic tectum) and the conversion of myocytes to the impulse conducting cell linage (heart).
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Daniel L. Minor, Ph.D.
Assistant Professor of Biochemistry & Biophysics
Research Interests:
Membrane proteins; potassium channels, calcium channels
Summary:
An electrical impulse drives each heartbeat. Generation of such signals requires the concerted action of ion channel proteins and the molecules that modulate their activity. Together, these proteins form the machinery that allows ions such as sodium, potassium, and calcium to move into and out of cells to make electrical signals in the heart and brain. Our lab is interested in understanding the fundamental molecular architecture of ion channels. This information is essential for understanding how they work, for developing new therapeutics to control their functions, and to understand how disease causing mutations cause problems such as arrythmias, epilepsy, and deafness. Despite decades of study by functional methods, a scarcity of high-resolution structural information and a lack of specific inhibitors for many types of channels limit our knowledge of how these molecules work. Understanding ion channels ultimately requires a high-resolution structural description of the channel proteins, their regulatory factors, and the conformational changes that accompany channel action. We are approaching this problem from the perspective of structural biology. Because channels are membrane proteins, a difficult class to investigate with any single structural technique, our efforts are directed at a multidisciplinary approach that involves both genetic, biochemical, electrophysiological, and X-ray crystallographic approaches for studying ion channel structure and function.
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Robin M. Shaw, M.D., Ph.D.
Assistant Professor of Medicine
Research Interests:
Cardiac Electrophysiology, Ion Channels, Arrhythmia, Sudden Cardiac Death, Heart Failure
Summary:
The basic function of the heart is to work as a pump, circulating blood through the lungs and the rest of the body. For the heart to work properly, the function of millions of individual heart cells needs to be coordinated each second to act in synchrony. In the normal heart, a biological electrical system exists to coordinate the heart cells and consists of ion channels that regulate the flow of sodium, calcium and potassium ions in and out of cells. The collective movement of these molecules in and out of these ion channels creates the signals for the cells to contract. In the diseased heart, damage from blocked heart arteries leads to improper cellular expression of the ion channels, which results in dangerous heart rhythms such as the ÒflatlineÓ of sudden cardiac death. In this situation, the biological electrical system is Òshort circuitedÓ, and millions of cells are contracting randomly, leaving a nonworking pump. There are 200,000 to 400,000 cases of sudden cardiac death in the United States each year. In addition, cumulative damage to the heart over time can result in the poorly coordinated and weakened contraction of congestive heart failure, which affects five million Americans. For these reasons, we are very interested in ion channel regulation in both normal and damaged heart cells. We use a cell biology based approach to study the movement of the proteins that form the channels as they travel from their site of formation to their placement and specific locations on the heart cell membrane. Specific projects in the laboratory involve studying how cells lose communication with each other and with their signals to contract by altering the delivery of ion channels to their proper functional subregion on the cell membrane. The ultimate goal is to use the insights gained by these studies to develop ion channel targeted therapeutic interventions that decrease the incidence and impact of sudden cardiac death and heart failure.
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