Vasoregulation by the Cav1.2 channel C-terminus

Summary

Principal Investigator: Kirk W Evanson
Abstract: DESCRIPTION (provided by applicant): Resistance-size cerebral arteries modulate brain regional blood pressure and flow. Arterial smooth muscle cell voltage-dependent calcium (CaV1.2) channels are key regulators of vascular contractility. Vascular CaV1.2 channels are activated by membrane depolarization and vasoconstrictor agonists, leading to an increase in intracellular calcium ([Ca2+]i) concentration and vasoconstriction. CaV1.2 channels can undergo enzymatic cleavage, yielding truncated, short-form CaV1.2 channels and a C-terminal protein fragment (CCT). Whether CCT exists in arterial smooth muscle cells and regulates vascular contractility is unclear. This application stems from novel preliminary data indicating that CCT exhibits nuclear localization and attenuates functional CaV1.2 expression in cerebral artery smooth muscle cells. Preliminary data also indicate that vasoconstrictors reduce CCT protein to elevate CaV1.2 channel expression and induce vasoconstriction. The central hypothesis of this proposal is that the CCT controls functional CaV1.2 channel expression and plasma membrane currents in cerebral artery smooth muscle cells. Aim 1 will investigate the hypothesis that the truncated CaV1.2 channel C-terminus inhibits CaV1.2transcription, surface CaV1.2 channel expression, and CaV1.2currents in arterial smooth muscle cells. Aim 2 will examine the hypothesis that vasoconstrictors control CaV1.2 channel expression and activity by modulating the total amount and nuclear localization of CCT in arterial smooth muscle cells. Aim 3 will test the hypothesis that the CCT regulates arterial smooth muscle cell [Ca2+]i, thereby modulating contractility. Techniques to be used include real-time PCR, Western blotting, expression of recombinant CCT, RNA interference, immunofluorescence and immunofluorescence resonance energy transfer (immunoFRET), patch-clamp electrophysiology, calcium imaging, and pressurized artery myography. This research will reveal novel mechanisms of vascular contractility regulation by the CaV1.2 channel C-terminus.
Funding Period: 2012-07-01 - 2015-06-30
more information: NIH RePORT

Research Grants

  1. Vasoregulation by IP3 receptor coupling to TRPC channels
    Adebowale Adebiyi; Fiscal Year: 2013
  2. Molecular Mechanisms of Blood Cell Transfusion
    LESLIE ERIC SILBERSTEIN; Fiscal Year: 2013
  3. Vascular control by K+ channel trafficking
    Jonathan H Jaggar; Fiscal Year: 2013
  4. Arterial Smooth Muscle Chloride Channels
    Jonathan H Jaggar; Fiscal Year: 2013
  5. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
  6. Flow-induced coronary vasospasm in diabetic patients
    Zsolt Bagi; Fiscal Year: 2013
  7. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
  8. Ethanol actions on slo channels from arteries vs. brain
    Alex M Dopico; Fiscal Year: 2013
  9. Role of Sphingolipids in the Pathobiology of Lung Injury
    Viswanathan Natarajan; Fiscal Year: 2013
  10. STIM-Dependent Signaling in Cardiac Pathophysiology
    Salvatore Mancarella; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Vasoregulation by IP3 receptor coupling to TRPC channels
    Adebowale Adebiyi; Fiscal Year: 2013
    ..Experiments to study these aims will integrate techniques performed at molecular, cellular, and intact tissue levels, including Ca2+ imaging, FRET, electrophysiology, pressurized artery myography, and gene suppression. ..
  2. Molecular Mechanisms of Blood Cell Transfusion
    LESLIE ERIC SILBERSTEIN; Fiscal Year: 2013
    ..Collectively, this program will yield significant insight and information that will directly translate into optimization of existing cell therapies and development of new ones. ..
  3. Vascular control by K+ channel trafficking
    Jonathan H Jaggar; Fiscal Year: 2013
    ..This proposal will provide significant novel information concerning cerebral artery contractility regulation by physiological and pathological mechanisms that control BKCa channel surface expression. ..
  4. Arterial Smooth Muscle Chloride Channels
    Jonathan H Jaggar; Fiscal Year: 2013
    ....
  5. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  6. Flow-induced coronary vasospasm in diabetic patients
    Zsolt Bagi; Fiscal Year: 2013
    ..Data obtained in this project will also help to develop novel avenues for effective therapeutic strategies, such as the use of prostanoid inhibitors at the time of PCI, to prevent no reflow in patients with T2-DM. ..
  7. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  8. Ethanol actions on slo channels from arteries vs. brain
    Alex M Dopico; Fiscal Year: 2013
    ..abstract_text> ..
  9. Role of Sphingolipids in the Pathobiology of Lung Injury
    Viswanathan Natarajan; Fiscal Year: 2013
    ..Together, this PPG addresses critical needs (insights, biomarkers, therapies) in ALI and RILI facilitating development of pharmacogenomic assays and SIP-based therapies for inflammatory lung injury. ..
  10. STIM-Dependent Signaling in Cardiac Pathophysiology
    Salvatore Mancarella; Fiscal Year: 2013
    ..The multidisciplinary approach (biochemical and physiological) proposed will ensure a high quality training of the candidate. ..
  11. Calcium signaling in the cerebrovascular unit in health and disease
    Mark T Nelson; Fiscal Year: 2013
    ..The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease. ..
  12. Vascular Interactions of Estrogen Receptor GPR30 and the Renin-Angiotensin System
    Sarah Hoffmann Lindsey; Fiscal Year: 2013
    ..These studies will establish the regulation of'Vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system. ..
  13. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  14. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  15. VASOMOTOR CONTROL OF DESCENDING VASA RECTA
    Thomas L Pallone; Fiscal Year: 2013
    ..We will test whether upregulation of HO-1 normalizes CaV conductance and membrane potential in Dahl/SS rats and examine the ability of intramedullary CaV blockade to augment perfusion of the medulla in those animals. ..
  16. Pregnancy/NO Induced Changes in UAE Ca2+Signaling
    Ian M Bird; Fiscal Year: 2013
    ..Having more complete knowledge of how cell function is regulated in pregnancy will certainly take us one step closer to overcoming this potentially devastating disease that effects so many in this country and beyond. ..
  17. Calcium channels in arterial smooth muscle cells
    Jonathan H Jaggar; Fiscal Year: 2013
    ..2 channels are expressed in arterial smooth muscle cells, and that the molecular composition of these channels is altered in hypertension, leading to vasoconstriction. ..
  18. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  19. MicroRNA to decrease vascular CaV1.2 in hypertension
    Philip T Palade; Fiscal Year: 2013
    ..A longer lasting therapy with fewer side effects may be extremely beneficial for the >40 million Americans whose hypertension is not properly managed. ..
  20. Alpha-2 Na+ Pumps, [Ca2+], Arterial Contraction &Hypertension
    Mordecai P Blaustein; Fiscal Year: 2013
    ..We also will determine the effects of chronic ouabain treatment on a2, NCX1 and TRPC6 protein expression in primary cultured hASMCs, and whether this effect is antagonized by digoxin and certain other CTS. ..
  21. TRP Channel-Dependent Regulation of Arterial Tone
    Scott Earley; Fiscal Year: 2013
    ..abstract_text> ..
  22. KCNQ Channels and Vasoconstrictor Signal Transduction
    Kenneth L Byron; Fiscal Year: 2013
    ....
  23. PSD95 scaffolding of vascular K+ channels in hypertension
    Sung W Rhee; Fiscal Year: 2013
    ....
  24. Vascular Smooth Muscle Function in Pulmonary Hypertension
    Nikki L Jernigan; Fiscal Year: 2013
    ..Ultimately, such knowledge has the potential to provide new directions in pulmonary hypertension therapy. ..
  25. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  26. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  27. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  28. Vasodilation via selective pharmacological targeting of BK channel beta1 subunits
    Alex M Dopico; Fiscal Year: 2013
    ..abstract_text> ..