Faculty Opinions recommendation of Effects of ginger and its constituents on airway smooth muscle relaxation and calcium regulation.

Epoxyeicosatrienoic acids (EETs) are produced from arachidonic acid via the cytochrome P-450 epoxygenase pathway. EETs are able to modulate smooth muscle tone by increasing K+ conductance, hence generating hyperpolarization of the tissues. However, the molecular mechanisms by which EETs induce smooth muscle relaxation are not fully understood. In the present study, the effects of EETs on airway smooth muscle (ASM) were investigated using three electrophysiological techniques. 8,9-EET and 14,15-EET induced concentration-dependent relaxations of the ASM precontracted with a muscarinc agonist (carbamylcholine chloride), and these relaxations were partly inhibited by 10 nM iberiotoxin (IbTX), a specific large-conductance Ca2+-activated K+ (BKCa) channel blocker. Moreover, 3 μM 8,9- or 14,15-EET induced hyperpolarizations of −12 ± 3.5 and −16 ± 3 mV, with EC50 values of 0.13 and 0.14 μM, respectively, which were either reversed or blocked on addition of 10 nM IbTX. These results indicate that BKCa channels are involved in hyperpolarization and participate in the relaxation of ASM. In addition, complementary experiments demonstrated that 8,9- and 14,15-EET activate reconstituted BKCa channels at low free Ca2+ concentrations without affecting their unitary conductance. These increases in channel activity were IbTX sensitive and correlated well with the IbTX-sensitive hyperpolarization and relaxation of ASM. Together these results support the view that, in ASM, the EETs act through an epithelium-derived hyperpolarizing factorlike effect.

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Opsin 3–Gαs Promotes Airway Smooth Muscle Relaxation Modulated by G Protein Receptor Kinase 2

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2020-0392oc ◽

2021 ◽

Vol 64 (1) ◽

pp. 59-68

Author(s):

Amy D. Wu ◽

William Dan ◽

Yi Zhang ◽

Shruti Vemaraju ◽

Brian A. Upton ◽

...

Keyword(s):

Smooth Muscle ◽

G Protein ◽

Airway Smooth Muscle ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation ◽

Receptor Kinase ◽

Protein Receptor

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Basenji-greyhound dog: increased m2 muscarinic receptor expression in trachealis muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.268.6.l935 ◽

1995 ◽

Vol 268 (6) ◽

pp. L935-L940 ◽

Cited By ~ 1

Author(s):

C. W. Emala ◽

A. Aryana ◽

M. A. Levine ◽

R. P. Yasuda ◽

S. A. Satkus ◽

...

Keyword(s):

Smooth Muscle ◽

Adenylyl Cyclase ◽

Muscarinic Receptor ◽

Airway Smooth Muscle ◽

Muscle Relaxation ◽

Receptor Expression ◽

Smooth Muscle Relaxation ◽

Muscarinic Agonists ◽

M2 Muscarinic Receptor ◽

Muscarinic M2 Receptors

Airway smooth muscle from asthmatic humans and from the Basenji-greyhound dog (BG) dog is hyporesponsive to beta-adrenergic agonist stimulation. Because adenylyl cyclase is under dual regulation in airway smooth muscle, we compared muscarinic receptor-coupled inhibition of adenylyl cyclase in airway smooth muscle from BG and mongrel dogs. Inhibition of forskolin-stimulated adenylyl cyclase activity by the muscarinic M2 agonist oxotremorine was greater in airway smooth muscle membranes from BG compared with mongrel controls. Quantitative immunoprecipitation studies showed increased numbers of m2 but not m3 muscarinic receptors in the BG airway smooth muscle. The enhanced ability of muscarinic agonists to inhibit adenylyl cyclase in BG airway smooth muscle may be due to the greater numbers of muscarinic m2 receptors, which may account in part for impaired airway smooth muscle relaxation in the BG model of airway hyperresponsiveness.

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G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00255.2003 ◽

2004 ◽

Vol 286 (2) ◽

pp. L312-L319 ◽

Cited By ~ 44

Author(s):

J. K. L. Walker ◽

R. R. Gainetdinov ◽

D. S. Feldman ◽

P. K. McFawn ◽

M. G. Caron ◽

...

Keyword(s):

Smooth Muscle ◽

G Protein ◽

Muscarinic Receptor ◽

Airway Smooth Muscle ◽

Muscarinic Receptors ◽

Muscle Relaxation ◽

Receptor Activation ◽

Smooth Muscle Relaxation ◽

Airway Responses ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M2 muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene ( GRK5- /-) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5- /- and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from β2-adrenergic receptor activation were diminished in GRK5- /- mice. These data suggest that M2 muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5- /- mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.

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Nitric Oxide and Vasoactive Intestinal Peptide as Co-transmitters of Airway Smooth-Muscle Relaxation

CHEST Journal ◽

10.1378/chest.124.3.1067 ◽

2003 ◽

Vol 124 (3) ◽

pp. 1067-1072 ◽

Cited By ~ 24

Author(s):

Nadia A. Hasaneen ◽

Hussein D. Foda ◽

Sami I. Said

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Vasoactive Intestinal Peptide ◽

Airway Smooth Muscle ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation

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The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00235.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. L69-L78 ◽

Cited By ~ 48

Author(s):

Padmini Komalavilas ◽

Raymond B. Penn ◽

Charles R. Flynn ◽

Jeffrey Thresher ◽

Luciana B. Lopes ◽

...

Keyword(s):

Smooth Muscle ◽

Heat Shock ◽

Airway Smooth Muscle ◽

Fluorescent Protein ◽

Muscle Relaxation ◽

Stress Fibers ◽

Smooth Muscle Relaxation ◽

Related Protein ◽

Kinase Substrate ◽

Pka Pathway

Activation of the cAMP/cAMP-dependent PKA pathway leads to relaxation of airway smooth muscle (ASM). The purpose of this study was to examine the role of the small heat shock-related protein HSP20 in mediating PKA-dependent ASM relaxation. Human ASM cells were engineered to constitutively express a green fluorescent protein-PKA inhibitory fusion protein (PKI-GFP) or GFP alone. Activation of the cAMP-dependent signaling pathways by isoproterenol (ISO) or forskolin led to increases in the phosphorylation of HSP20 in GFP but not PKI-GFP cells. Forskolin treatment in GFP but not PKI-GFP cells led to a loss of central actin stress fibers and decreases in the number of focal adhesion complexes. This loss of stress fibers was associated with dephosphorylation of the actin-depolymerizing protein cofilin in GFP but not PKI-GFP cells. To confirm that phosphorylated HSP20 plays a role in PKA-induced ASM relaxation, intact strips of bovine ASM were precontracted with serotonin followed by ISO. Activation of the PKA pathway led to relaxation of bovine ASM, which was associated with phosphorylation of HSP20 and dephosphorylation of cofilin. Finally, treatment with phosphopeptide mimetics of HSP20 possessing a protein transduction domain partially relaxed precontracted bovine ASM strips. In summary, ISO-induced phosphorylation of HSP20 or synthetic phosphopeptide analogs of HSP20 decreases phosphorylation of cofilin and disrupts actin in ASM, suggesting that one possible mechanism by which HSP20 mediates ASM relaxation is via regulation of actin filament dynamics.

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