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People Detail

Faculty Biography For:

Stuart Dryer
John and Rebecca Moores Professor and Chair
Ph.D., St. Louis University, 1985

Biology and Biochemistry Department
University of Houston
Houston, Texas 77204-5001

Office: SR2 242E
Phone: (713) 743-2697
sdryer@uh.edu
Curriculum Vitae  

Regulation of ion channels in podocytes and their role in glomerular filtration and glomerular diseases
Podocytes are unusual cells that look a bit like neurons. They have a stellate shape with numerous processes that extend from an oblong cell body and which terminate in specialized structures known as foot processes. As expected from their shape, they share many developmental and cell biological processes in common with neurons and certain glia. However, they are not excitable, and they are better described as highly specialized pericytes. Podocytes lie on the urinary surface of the glomerular basement and their foot processes line the surface of glomerular capillaries in the vertebrate kidney. They are essential components of the glomerular filtration apparatus; indeed, the most common kidney diseases that progress to end-stage renal failure, including diabetes mellitus, are associated with early damage or dysfunction of podocytes. A main goal of our research is to understand the role of ionic channels and calcium dynamics in cell signaling in podocytes, and to understand how their dysfunction contributes to glomerular pathology and kidney failure. Two classes of channels of special importance include members of the canonical transient receptor potential (TRPC) channels, and large conductance calcium-activated K channels (BK channels). We and others have shown that these proteins physically interact with many proteins in the podocytes foot processes, including nephrin, Neph1, MAGI-1, podocin, the TRPC6 and TRPC3 cation channels, and, most recently synaptopodin. Several of these proteins are concentrated at specialized domains of foot processes known as slit diaphragms, where glomerular filtration actually takes place. This has led to a new line of investigation in our laboratory currently funded by the NIH. We have demonstrated that the ion channels of podocytes are regulated by processes that are quite similar to those that we have previously described in neurons. Of particular interest is the observation that podocyte BK channels are regulated by insulin, a hormone that is essential for the normal function of the kidney glomerulus, and that these channels are markedly upregulated during the hyperfiltration stage (early stage) of nephropathy associated with type 2 diabetes. We are now working to understand regulation of BK and TRPC6 trafficking to the cell surface, the functional significance of their interactions with other proteins in the glomerular slit diaphragm, and the functional relationship between TRPC6 and BK channels in the overall regulation of calcium dynamics in podocytes. We are also interested in the role of these channels in cell signaling and the overall integrative physiology of glomerular filtration. We are carrying out this work in collaboration with several other laboratories in the US and in Europe. More recently we have expanded our interest to other renal channels, such as ENaC channels that are involved in regulation of the function of the cortical collecting ducts of renal tubules, and calcium-permeable NMDA receptors, which we have recently characterized in podocytes and in other renal cell types. NMDA receptors may play a role in normal glomerular physiology, but their excessive activation may be a contributing factor to several progressive glomerulodegenerative diseases.

Growth factors and the developmental regulation of neuronal excitability
For many years we examined the mechanisms that allow vertebrate neurons to acquire a specialized electrophysiological phenotype during embryonic development. This research is motivated by the fact that the electrophysiological properties, such as the spike waveform and repetitive firing pattern, vary greatly among different populations of mature neurons. These traits control the input-output relationships of excitable cells and thereby determine how a given neuron will process information within a mature circuit. Because these properties are subject to modulation, they also determine how the properties of a circuit can change over longer time scales as a result of use. Moreover, in some cases, changes in electrical firing patterns at critical stages of development are essential for the formation and/or refinement of neuronal networks.

The electrophysiological characteristics of neurons are determined primarily by the ensemble of different types of ionic channels expressed in the plasma membrane. Among the various ionic channels, it is the K channels that are by far the most diverse and play a large role in shaping the resting level of excitability, the temporal pattern of spike discharge, and the action potential waveform. Many of the K channels expressed in neurons are not essential for excitability, and their principal role is to regulate the temporal pattern of spike discharge. This class of channel is of special interest in my laboratory.

How does a neuron determine which types of channels to express and when to express them? We have been addressing this question in identified populations of developing vertebrate neurons, especially cells of the embryonic chick autonomic nervous system and more recently in motoneurons of the lumbar spinal cord. We have found that the expression of a normal ensemble of ionic channels in these cells is critically dependent on interactions with other cell types, including the target tissues and the presynaptic afferent nerve fibers. In embryonic chick ciliary ganglion neurons, an especially tractable model system, we have identified several molecules secreted from target tissues and presynaptic cells that regulate the developmental expression of certain ionic channels, and we are investigating their mechanisms of action. For several reasons, we focused on large-conductance BK channels encoded by the Slo1 gene, and transient A-type K channels encoded by the Kv4.2 and Kv4.3 genes. We have identified several growth factors that endogenously regulate K channel expression in chick ciliary ganglion neurons in vivo and in vitro, including transforming growth factor-beta1, transforming growth factor-3 and -neuregulin-1 (NRG1). The two TGF-beta isoforms are expressed in the target tissues of ciliary ganglion neurons, and rather surprisingly exert opposing effects on the developmental expression of BK channels. NRG1 appears to be secreted from the preganglionic cells that innervate the ciliary ganglion, and is required for normal BK channel expression. Ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF) and a closely related molecule known as nurturin play a role in the developmental regulation of A-type K channels in ciliary ganglion neurons. All three of these factors are expressed in the target tissues of ciliary neurons albeit at different developmental stages.

More recent work in our laboratory focused on the transduction mechanisms whereby the TGF-betas and NRG1 regulate the electrophysiological differentiation of vertebrate neurons. We have shown that several pathways, including Erk and p38 MAP kinase cascades, as well as the PI3 kinase/Akt cascades, are involved in NRG1 and TGF-beta signaling in ciliary ganglion neurons. Moreover, we have shown that these factors regulate functional expression of BK channels primarily by controlling channel trafficking to the plasma membrane, an effect that requires activation of several small GTPase molecules (such as ARF1 and ARF6) and remodeling of the neuronal cytoskeleton. In this regard, we have observed that a cortical actin layer functions as a barrier to the insertion of BKa channels into the plasma membrane, and that trophic factors exert complex effects on the dynamics of the cortical actin barrier as well as its interactions with BK channels.

Other recent work from our laboratory has shown that BK channels occur in multiple intracellular compartments within ciliary neurons. These include a pool located in the ER and Golgi apparatus, and a second more distal pool located in post-Golgi compartments that are presumably close to the cortical actin barrier. NRG1 preferentially evokes mobilization of the post-Golgi pool of BK channels, whereas TGF-beta1 preferentially mobilizes channels in the ER and Golgi. The post-Golgi pool appears to be limited in capacity and is fairly readily depleted. In addition, channels in the plasma membrane appear to turn over fairly quickly. The reasons why BK channels occur in different cellular compartments and the mechanisms underlying their differential regulation are currently under investigation. One possibility is that the different pools contain different Slo1 channel isoforms produced as a result of alternative splicing at the extreme C-terminal. As part of the program to test this hypothesis, we are currently looking for binding partners that bind to the Slo1 C-terminals, with a special interest in identifying binding partners that are isoform specific. It bears noting that all of the BK isoforms in ciliary ganglion neurons and in podocytes can interact with actin. We are also examining the role of endocytosis as a mechanism to control steady-state levels of functional BKCa channels in the plasma membrane.

Anderson, M., Suh, J. M., Kim, E. Y. & Dryer, S. E. (2010). Functional NMDA receptors with atypical properties are expressed in podocytes. American Journal of Physiology-Cell Physiology in press.

Dryer. S. E. & Reiser, J. (2010). TRPC6 channels and their binding partners in podocytes: Role in glomerular filtration and pathophysiology. American Journal of Physiology-Renal Physiology in press.

Kim, E. Y., Suh, J. M., Chiu, Y.-S. & Dryer, S. E. (2010). Regulation of podocyte BKCa channels by synaptopodin, Rho, and actin microfilaments. American Journal of Physiology -Renal Physiology 299: F594-604.

Chiu, Y.-S., Alvarez-Baron, C., Kim, E. Y. & Dryer, S. E. (2010). Dominant-negative regulation of cell surface expression by a pentapeptide motif at the extreme COOH-terminal of a Slo1 calcium-activated potassium channel splice variant. Molecular Pharmacology 77: 497-507.

Reisenauer, M. R., Anderson, M., , Huang, L., Zhang, Z., Zhou, Q., Kone, B. C., Morris, A. P., LeSage, G. D., Dryer, S. E. & Zhang, W. (2009). AF17 competes with AF9 for binding to Dot1a to upregulate transcription of epithelial Na channel . Journal of Biological Chemistry 284: 35659-69.

Kim, E.Y., Chiu Y. H. & Dryer, S. E. (2009). Neph1 regulates the steady-state surface expression of Slo1 Ca2 -activated K channels: Different effects in embryonic neurons and podocytes. American Journal of Physiology  Cell Physiology 297: C1379-88.

Jha, S. & Dryer, S. E. (2009). The 1-subunit of Na /K -ATPase interacts with BKCa channels and affects their steady-state expression on the cell surface. FEBS Letters 583: 3109-14.

Ridgway, L. D., Kim E. Y. & Dryer, S. E. (2009).  MAGI-1 interacts with Slo1 channel proteins and suppresses Slo1 expression on the cell surface.  American Journal of Physiology  Cell Physiology 297: C55-65.

Kim, E. Y., Alvarez-Baron, C. P. & Dryer, S. E. (2009).  Canonical transient receptor potential channel (TRPC)3 and TRPC6 associate with large-conductance Ca2 -activated K (BKCa) channels: role in BKCa trafficking to the surface of cultured podocytes. Molecular Pharmacology 75: 466-77.

Kim, E. Y., Choi, K. & Dryer, S. E. (2008).  Nephrin binds to the COOH-terminal of a large-conductance calcium-activated potassium channel isoform and regulates its expression on the cell surface. American Journal of Physiology  Renal Physiology 295: F235-46.

Zou S, Jha S, Kim EY, Dryer SE. (2008). A novel actin-binding domain on Slo1 calcium-activated potassium channels is necessary for their expression in the plasma membrane. Molecular Pharmacology,73(2):359-68.

Zou S, Jha S, Kim EY, Dryer SE. (2008). The beta 1 subunit of L-type voltage-gated Ca2 channels independently binds to and inhibits the gating of large-conductance Ca2 -activated K channels. Molecular Pharmacology, 73(2):369-78.

Kim, E. Y., Ridgway, L. D., Zou, S., Chiu, Y.-H. & Dryer, S. E (2007). Alternatively spliced C-terminal domains regulate the surface expression of large conductance calcium-activated potassium (BKCa) channels. Neuroscience 146: 1652-61.

Chen SK, Ko GY, Dryer SE. (2007). Somatostatin peptides produce multiple effects on gating properties of native cone photoreceptor cGMP-gated channels that depend on circadian phase and previous illumination. The Journal Of Neuroscience, 27(45):12168-75.

Ko ML, Liu Y, Dryer SE, Ko GY. (2007). The expression of L-type voltage-gated calcium channels in retinal photoreceptors is under circadian control. Journal Of Neurochemistry, 103(2):784-92.

Scott SP, Shea PW, Dryer SE. (2007). Mapping ligand interactions with the hyperpolarization activated cyclic nucleotide modulated (HCN) ion channel binding domain using a soluble construct. Biochemistry, 46(33):9417-31.

Kim EY, Ridgway LD, Dryer SE. (2007). Interactions with filamin A stimulate surface expression of large-conductance Ca2 -activated K channels in the absence of direct actin binding. Molecular Pharmacology, 72(3):622-30.

Kim EY, Zou S, Ridgway LD, Dryer SE. (2007). Beta1-subunits increase surface expression of a large-conductance Ca2 -activated K channel isoform. Journal Of Neurophysiology, 97(5):3508-16.

Chae KS, Ko GY, Dryer SE. (2007). Tyrosine phosphorylation of cGMP-gated ion channels is under circadian control in chick retina photoreceptors. Investigative Ophthalmology & Visual Science, 48(2):901-6.

Bryan RM Jr, You J, Phillips SC, Andresen JJ, Lloyd EE, Rogers PA, Dryer SE, Marrelli SP. (2006). Evidence for two-pore domain potassium channels in rat cerebral arteries. American Journal Of Physiology. Heart And Circulatory Physiology, 291(2):H770-80.

Chae KS, Dryer SE. (2005). The p38 mitogen-activated protein kinase pathway negatively regulates Ca2 activated K channel trafficking in developing parasympathetic neurons. Journal Of Neurochemistry, 94(2):367-79.

Chae KS, Oh KS, Dryer SE. (2005). Growth factors mobilize multiple pools of KCa channels in developing parasympathetic neurons: role of ADP-ribosylation factors and related proteins. Journal Of Neurophysiology, 94(2):1597-605.

Krishnan P, Dryer SE, Hardin PE. (2005). Measuring circadian rhythms in olfaction using electroantennograms. Methods in Enzymology, 393:495-508.

Ko GY, Ko M, Dryer SE. (2004). Circadian and cAMP-dependent modulation of retinal cone cGMP-gated channels does not require protein synthesis or calcium influx through L-type channels. Cognitive Brain Research, 1021(2):277-80.

Hardin PE, Krishnan B, Houl JH, Zheng H, Ng FS, Dryer SE, Glossop NR. (2003). Central and peripheral circadian oscillators in Drosophila. Novartis Foundation Symposium, 253:140-50.

Dryer SE, Lhuillier L, Cameron JS, Martin-Caraballo M. (2003). Expression of K(Ca) channels in identified populations of developing vertebrate neurons: role of neurotrophic factors and activity. Journal Of Physiology, Paris, 97(1):49-58.

Dryer SE. (2003). Molecular identification of the Na -activated K channel. Neuron, 37(5):727-8.

Krishnan, B., Dryer, S. E. & Hardin, P. E. (1999). Circadian rhythms in olfactory responses of Drosophila melanogaster. Nature 400: 375-379.

Cameron, J., Lhuillier, L., Subramony, P. & Dryer, S. E. (1998). Developmental regulation of neuronal K channels by target-derived TGF-beta in vivo and in vitro. Neuron 21: 1045-1053.