Paula Q. Barrett

GetPhoto.ashx?photo=pqb4b_794

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 Interests

Regulation of low-voltage activated T-type Ca2+ channel activity by kinases and heterotrimeric G-proteins and their roles in physiological responses.

Research Description

Calcium channel regulation and the control of cell function
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

Calcium channel regulation and the control of cell functionIntracellular 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.

Training

  • Basic Cardiovascular Research Training Grant
  • Training in the Pharmacological Sciences

Selected Publications

Freedman BD, Kempna PB, Carlone DL, Shah MS, Guagliardo NA, Barrett PQ, Gomez-Sanchez CE, Majzoub JA, Breault DT, Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells., 2013; Developmental cell. 26(6) 666-73. PMID: 24035414 | PMCID: PMC3791142

Guagliardo NA, Yao J, Hu C, Barrett PQ, Minireview: aldosterone biosynthesis: electrically gated for our protection., 2012; Endocrinology. 153(8) 3579-86. PMID: 22689262 | PMCID: PMC3404360

Jung J, Barrett PQ, Eckert GJ, Edenberg HJ, Xuei X, Tu W, Pratt JH, Variations in the potassium channel genes KCNK3 and KCNK9 in relation to blood pressure and aldosterone production: an exploratory study., 2012; The Journal of clinical endocrinology and metabolism. 97(11) E2160-7. PMID: 22893713 | PMCID: PMC3485591

Hu C, Rusin CG, Tan Z, Guagliardo NA, Barrett PQ, Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators., 2012; The Journal of clinical investigation. 122(6) 2046-53. PMID: 22546854 | PMCID: PMC3966877

Guagliardo NA, Yao J, Hu C, Schertz EM, Tyson DA, Carey RM, Bayliss DA, Barrett PQ, TASK-3 channel deletion in mice recapitulates low-renin essential hypertension., 2012; Hypertension. 59(5) 999-1005. PMID: 22493079 | PMCID: PMC3357084

Guagliardo NA, Yao J, Bayliss DA, Barrett PQ, TASK channels are not required to mount an aldosterone secretory response to metabolic acidosis in mice., 2010; Molecular and cellular endocrinology. 336(1) 47-52. PMID: 21111026 | PMCID: PMC3057342

DePuy SD, Yao J, Hu C, McIntire W, Bidaud I, Lory P, Rastinejad F, Gonzalez C, Garrison JC, Barrett PQ, The molecular basis for T-type Ca2+ channel inhibition by G protein beta2gamma2 subunits., 2006; Proceedings of the National Academy of Sciences of the United States of America. 103(39) 14590-5. PMID: 16973746 | PMCID: PMC1600004

Yao J, Davies LA, Howard JD, Adney SK, Welsby PJ, Howell N, Carey RM, Colbran RJ, Barrett PQ, Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II., 2006; The Journal of clinical investigation. 116(9) 2403-12. PMID: 16917542 | PMCID: PMC1550277

Welsby PJ, Wang H, Wolfe JT, Colbran RJ, Johnson ML, Barrett PQ, A mechanism for the direct regulation of T-type calcium channels by Ca2+/calmodulin-dependent kinase II., 2003; The Journal of neuroscience : the official journal of the Society for Neuroscience. 23(31) 10116-21. PMID: 14602827

Wolfe JT, Wang H, Howard J, Garrison JC, Barrett PQ, T-type calcium channel regulation by specific G-protein betagamma subunits., 2003; Nature. 424(6945) 209-13. PMID: 12853961

Throckmorton D, Kurscheid-Reich D, Rosales OR, Rodriguez-Commes J, Lopez R, Sumpio B, Zhong Q, Ding KH, McCarthy R, Barrett PQ, Isales CM, Parathyroid hormone effects on signaling pathways in endothelial cells vary with peptide concentration., 2002; Peptides. 23(1) 79-85. PMID: 11814621

Wolfe JT, Wang H, Perez-Reyes E, Barrett PQ, Stimulation of recombinant Ca(v)3.2, T-type, Ca(2+) channel currents by CaMKIIgamma(C)., 2002; The Journal of physiology. 538(0) 343-55. PMID: 11790804 | PMCID: PMC2290082

Schrier AD, Wang H, Talley EM, Perez-Reyes E, Barrett PQ, alpha1H T-type Ca2+ channel is the predominant subtype expressed in bovine and rat zona glomerulosa., 2001; American journal of physiology. Cell physiology. 280(2) C265-72. PMID: 11208520

Barrett PQ, Lu HK, Colbran R, Czernik A, Pancrazio JJ, Stimulation of unitary T-type Ca(2+) channel currents by calmodulin-dependent protein kinase II., 2000; American journal of physiology. Cell physiology. 279(6) C1694-703. PMID: 11078683

Isales CM, Sumpio B, Bollag RJ, Zhong Q, Ding KH, Du W, Rodriguez-Commes J, Lopez R, Rosales OR, Gasalla-Herraiz J, McCarthy R, Barrett PQ, Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line., 2000; American journal of physiology. Endocrinology and metabolism. 279(3) E654-62. PMID: 10950835

Chen XL, Bayliss DA, Fern RJ, Barrett PQ, A role for T-type Ca2+ channels in the synergistic control of aldosterone production by ANG II and K+., 1999; The American journal of physiology. 276(5) F674-83. PMID: 10330049