Paula Q. Barrett
- Phone: 434-924-5454
- Fax: 434-982-3878
Primary Appointment
Professor, Pharmacology
Education
- BS, Physics, Marymount College (NY)
- MS, Health Physics, University of Rochester
- PhD, Biophysics, University of Rochester
Research Disciplines
Biophysics & Structural Biology, Cardiovascular Biology, Molecular Pharmacology, Translational Science
Research Description
Intracellular calcium is a universal signal mediating the actions of many hormones. During cell activation intracellular calcium rises dramatically, as the activities of calcium entry pathways are increased. Voltage-gated calcium channels prominently regulate the entry of calcium into cells. Their activity is regulated by voltage, and hormones. A subclass of these channels, the low-voltage-activated, T-type, calcium channel regulates action potential frequency in excitable cells and provides the calcium necessary for cell activation in non-excitable cells that maintain a relatively static negative membrane potential.
Low-voltage-activated calcium channels have been implicated in the pathogenesis of arrhythmias, epilepsy, diabetes, hypertension, and in the progression of congestive heart failure. Our laboratory is interested in delineating the signaling pathways that control the activity of this channel type and focuses on defining the molecular mechanisms underlying regulation and the relationship of channel activity to physiological function.
Regulation and role in aldosterone secretion
Using a combination of whole cell and single channel electrophysiologcial recording techniques, we have shown that both the activation of a kinase, calcium-calmodulin-dependent protein kinase II (CaMKII), and the activation of a G protein, Gi, induces a hyperpolarizing shift in the voltage-dependence of activation (opening) of the T-type calcium channel that results in an increase in channel current at negative potentials. We are currently using molecular biological techniques and clonal cell lines that express the T-type calcium channel to identify the sites of phosphorylation, the activating G protein subunit, and the sites of G protein interaction that underlie the stimulatory changes in channel gating. How these mechanisms interact during Angiotensin II stimulation and their physiological significance to the secretion of aldosterone is being pursued.
Regulation and role in insulin secretion
In neonatal and fetal tissues, CaMKII beta isoforms are abundantly expressed. Using a combination of immunogloical and molecular approaches we have identified a novel isoform of CaMKII in an insulin secreting cell line. We are investigating the consequences of activation of this novel isoform of CaMKII to the regulation of intracellular calcium, the modulation of T-type calcium channel activity and the secretion of insulin during physiological glucose stimulation.
Personal Statement
Low-voltage-activated calcium channels have been implicated in the pathogenesis of arrhythmias, epilepsy, diabetes, hypertension, and in the progression of congestive heart failure. Our laboratory is interested in delineating the signaling pathways that control the activity of this channel type and focuses on defining the molecular mechanisms underlying regulation and the relationship of channel activity to physiological function.
Regulation and role in aldosterone secretion
Using a combination of whole cell and single channel electrophysiologcial recording techniques, we have shown that both the activation of a kinase, calcium-calmodulin-dependent protein kinase II (CaMKII), and the activation of a G protein, Gi, induces a hyperpolarizing shift in the voltage-dependence of activation (opening) of the T-type calcium channel that results in an increase in channel current at negative potentials. We are currently using molecular biological techniques and clonal cell lines that express the T-type calcium channel to identify the sites of phosphorylation, the activating G protein subunit, and the sites of G protein interaction that underlie the stimulatory changes in channel gating. How these mechanisms interact during Angiotensin II stimulation and their physiological significance to the secretion of aldosterone is being pursued.
Regulation and role in insulin secretion
In neonatal and fetal tissues, CaMKII beta isoforms are abundantly expressed. Using a combination of immunogloical and molecular approaches we have identified a novel isoform of CaMKII in an insulin secreting cell line. We are investigating the consequences of activation of this novel isoform of CaMKII to the regulation of intracellular calcium, the modulation of T-type calcium channel activity and the secretion of insulin during physiological glucose stimulation.
Training
- Basic Cardiovascular Research Training Grant
- Training in the Pharmacological Sciences
Selected Publications
2022
Gancayco, C. A., Gerding, M. R., Breault, D. T., Beenhakker, M. P., Barrette, P. O., & Guagliardo, N. A. (2022). Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism. HYPERTENSION, 79(11), 2552-2564. doi:10.1161/HYPERTENSIONAHA.122.19557
2021
Narahari, A. K., Kreutzberger, A. J. B., Gaete, P. S., Chiu, Y. -H., Leonhardt, S. A., Medina, C. B., . . . Bayliss, D. A. (2021). ATP and large signaling metabolites flux through caspase-activated Pannexin 1 channels. ELIFE, 10. doi:10.7554/eLife.64787
Leng, S., Carlone, D. L., Guagliardo, N. A., Barrett, P. Q., & Breault, D. T. (2021). Rosette morphology in zona glomerulosa formation and function. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 530. doi:10.1016/j.mce.2021.111287
Barrett, P. Q., Guagliardo, N. A., & Bayliss, D. A. (2021). Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation. ANNUAL REVIEW OF PHYSIOLOGY, VOL 83, 83, 451-475. doi:10.1146/annurev-physiol-030220-113038
2020
DeLalio, L. J., Masati, E., Mendu, S., Ruddiman, C. A., Yang, Y., Johnstone, S. R., . . . Isakson, B. E. (2020). Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis. KIDNEY INTERNATIONAL, 98(3), 630-644. doi:10.1016/j.kint.2020.04.041
Leng, S., Pignatti, E., Khetani, R. S., Shah, M. S., Xu, S., Miao, J., . . . Breault, D. T. (2020). β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis. NATURE COMMUNICATIONS, 11(1). doi:10.1038/s41467-020-15332-7
Joksimovic, S. L., Evans, J. G., McIntire, W. E., Orestes, P., Barrett, P. Q., Jevtovic-Todorovic, V., & Todorovic, S. M. (2020). Glycosylation of CaV3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes. FRONTIERS IN CELLULAR NEUROSCIENCE, 14. doi:10.3389/fncel.2020.605312
Pignatti, E., Leng, S., Yuchi, Y., Borges, K. S., Guagliardo, N. A., Shah, M. S., . . . Breault, D. T. (2020). Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation. CELL REPORTS, 31(3). doi:10.1016/j.celrep.2020.107524
Guagliardo, N. A., Klein, P. M., Gancayco, C. A., Lu, A., Leng, S., Makarem, R. R., . . . Beenhakker, M. P. (2020). Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes. NATURE COMMUNICATIONS, 11(1). doi:10.1038/s41467-020-15408-4
Yang, T., He, M., Zhang, H., Barrett, P. Q., & Hu, C. (2020). L- and T-type calcium channels control aldosterone production from human adrenals. JOURNAL OF ENDOCRINOLOGY, 244(1), 237-247. doi:10.1530/JOE-19-0259
2019
Guagliardo, N. A., Yao, J., Stipes, E. J., Cechova, S., Le, T. H., Bayliss, D. A., . . . Barrett, P. Q. (2019). Adrenal Tissue-Specific Deletion of TASK Channels Causes Aldosterone-Driven Angiotensin II-Independent Hypertension. HYPERTENSION, 73(2), 407-414. doi:10.1161/HYPERTENSIONAHA.118.11962
2018
Jing, M., Zhang, P., Wang, G., Feng, J., Mesik, L., Zeng, J., . . . Li, Y. (2018). A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. NATURE BIOTECHNOLOGY, 36(8), 726-+. doi:10.1038/nbt.4184
2017
Yao, J., McHedlishvili, D., McIntire, W. E., Guagliardo, N. A., Erisir, A., Coburn, C. A., . . . Barrett, P. Q. (2017). Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells. HYPERTENSION, 70(2), 347-+. doi:10.1161/HYPERTENSIONAHA.116.08871
2016
Franceschini, N., Carty, C. L., Lu, Y., Tao, R., Sung, Y. J., Manichaikul, A., . . . Kooperberg, C. (2016). Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans. PLOS ONE, 11(10). doi:10.1371/journal.pone.0164132
Yang, T., Zhang, H. -L., Liang, Q., Shi, Y., Mei, Y. -A., Barrett, P. Q., & Hu, C. (2016). Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells. HYPERTENSION, 68(3), 785-+. doi:10.1161/HYPERTENSIONAHA.116.07094
Manichaikul, A., Rich, S. S., Allison, M. A., Guagliardo, N. A., Bayliss, D. A., Carey, R. M., & Barrett, P. Q. (2016). KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension. HYPERTENSION, 68(2), 356-+. doi:10.1161/HYPERTENSIONAHA.116.07564
Barrett, P. Q., Guagliardo, N. A., Klein, P. M., Hu, C., Breault, D. T., & Beenhakker, M. P. (2016). Role of voltage-gated calcium channels in the regulation of aldosterone production from zona glomerulosa cells of the adrenal cortex. JOURNAL OF PHYSIOLOGY-LONDON, 594(20), 5851-5860. doi:10.1113/JP271896
2013
Freedman, B. D., Kempna, P. B., Carlone, D. L., Shah, M. S., Guagliardo, N. A., Barrett, P. Q., . . . Breault, D. T. (2013). Adrenocortical Zonation Results from Lineage Conversion of Differentiated Zona Glomerulosa Cells. DEVELOPMENTAL CELL, 26(6), 666-673. doi:10.1016/j.devcel.2013.07.016
Orestes, P., Osuru, H. P., McIntire, W. E., Jacus, M. O., Salajegheh, R., Jagodic, M. M., . . . Todorovic, S. M. (2013). Reversal of Neuropathic Pain in Diabetes by Targeting Glycosylation of Cav3.2 T-Type Calcium Channels. DIABETES, 62(11), 3828-3838. doi:10.2337/db13-0813
2012
Guagliardo, N. A., Yao, J., Hu, C., Schertz, E. M., Tyson, D. A., Carey, R. M., . . . Barrett, P. Q. (2012). TASK-3 Channel Deletion in Mice Recapitulates Low-Renin Essential Hypertension (vol 59, pg 999, 2012). HYPERTENSION, 59(6), E59. doi:10.1161/HYP.0b013e31825b884a
Jung, J., Barrett, P. Q., Eckert, G. J., Edenberg, H. J., Xuei, X., Tu, W., & Pratt, J. H. (2012). Variations in the Potassium Channel Genes KCNK3 and KCNK9 in Relation to Blood Pressure and Aldosterone Production: An Exploratory Study. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 97(11), E2160-E2167. doi:10.1210/jc.2012-2196
Hu, C., Rusin, C. G., Tan, Z., Guagliardo, N. A., & Barrett, P. Q. (2012). Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators. JOURNAL OF CLINICAL INVESTIGATION, 122(6), 2046-2053. doi:10.1172/JCI61996
Guagliardo, N. A., Yao, J., Hu, C., & Barrett, P. Q. (2012). Minireview: Aldosterone Biosynthesis: Electrically Gated for Our Protection. ENDOCRINOLOGY, 153(8), 3579-3586. doi:10.1210/en.2012-1339
Guagliardo, N. A., Yao, J., Hu, C., Schertz, E. M., Tyson, D. A., Carey, R. M., . . . Barrett, P. Q. (2012). TASK-3 Channel Deletion in Mice Recapitulates Low-Renin Essential Hypertension. HYPERTENSION, 59(5), 999-+. doi:10.1161/HYPERTENSIONAHA.111.189662
2010
Guagliardo, N. A., Yao, J., Bayliss, D. A., & Barrett, P. Q. (2011). TASK channels are not required to mount an aldosterone secretory response to metabolic acidosis in mice. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 336(1-2), 47-52. doi:10.1016/j.mce.2010.11.017
Jung, J., Barrett, P. Q., Eckert, G. J., Tu, W., & Pratt, J. H. (2010). Association of Potassium Channel Genes, KCNK3 and KCNK9, with Blood Pressure and Serum Levels of Potassium and Aldosterone in African Americans. HYPERTENSION, 56(5), E94.