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Published Work
Processed Signals
2018
Introduction:Â Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disc, costamere and intercalated disc. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored.
Objectives:Â To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action.
Methods/Results: Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca2+ concentration ([Ca2+]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate …
2017
Rationale: Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored.
Objective: To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action.
Methods and Results: Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca2+concentration ([Ca2+]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate …
2017
Background Transient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs. Methods Hearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone. Results Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV …
2018
The discovery of transient receptor potential (TRP) ion channels in cardiac muscle has made them a promising target for the treatment of heart failure due to their activation markedly increasing cardiac contractility. Essential oils isolated from the plant Ferula iliensis (FiEOs) have great potential to be potent TRP agonists based on their structural homology to capsaicin (CAP) and allyl isothiocyanate (AITC), TRP vanilloid1 (TRPV1) and TRP ankyrin1 (TRPA1) agonists, respectively. HEK293 cells expressing TRPV1 or TRPA1 were used to assess the extent to which FiEOs were capable of activating TRPV1 or TRPA1 ion channels. Intracellular free Ca 2+ concentration ([Ca 2+] i) was measured to determine the magnitude of the response.(-)-Linalool,(-)-Limonene, and Camphene elicited transient increases in [Ca 2+] i similar to those observed with CAP in TRPV1-transfected HEK293 cells while α-Pinene oxide and α-Terpineol elicited transient increases in [Ca 2+] i similar to those observed with AITC in TRPA1-transfected HEK293 cells. No transient increases in [Ca 2+] i were observed by any of the FiEOs in non-transfected HEK293 cells, indicating the responses were specifically mediated by activation of TRPV1 or TRPA1 ion channels. Novel plant-based FiEOs that elicit TRPV1 and TRPA1 responses could potentially be viable and attractive products in the multi-billion-dollar alternative medicine industry for the treatment of a variety of types of heart failure. Further studies of FiEOs could lead to the development of natural therapeutic strategies for increased cardiac output via TRPV1 and TRPA1 stimulation.
2018
Transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is activated by a broad range of noxious stimuli. Cdk5, a member of the Cdk family, has recently been identified as a modulator of pain signaling pathways. In the current study, we investigated the extent to which Cdk5 modulates TRPA1 activity. Cdk5 inhibition was found to attenuate TRPA1 response to agonist in mouse DRG sensory neurons. Additionally, the presence of active Cdk5 was associated with increased TRPA1 phosphorylation in transfected HEK293 cells that was roscovitine-sensitive and absent in the mouse mutant S449A full-length channel. Immunopurified Cdk5 was observed to phosphorylate human TRPA1 peptide substrate at S448A in vitro. Our results point to a role for Cdk5 in modulating TRPA1 activity.