Carotid dysfunction in senescent female mice is mediated by increased α-adrenoceptor activity and COX-derived vasoconstrictor prostanoids.

α-Adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular diseases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardiovascular dysfunction, including stroke. Nevertheless, there is little information directly associating adrenergic receptor dysfunction in the blood vessels of aged females.

FK506 impairs neutrophil migration that results in increased polymicrobial sepsis susceptibility.

Objective: This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis.

Methods: Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wild-type (WT) mice and mice deficient in the gene Nfat1 (Nfat1) in the C57BL/6 background.

Angiotensin II Type 1 Receptor Tachyphylaxis Is Defined by Agonist Residence Time.

Several GPCRs (G-protein-coupled receptors) have been reported to exhibit tachyphylaxis, which is an acute loss of functional receptor response after repeated stimuli with an agonist. GPCRs are important clinical targets for a wide range of disorders. Therefore, elucidation of the ligand features that contribute to receptor tachyphylaxis and signaling events underlying this phenomenon is important for drug discovery and development.

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans.

The AT1 receptor (AT1R) has a major role in the Renin-Angiotensin System, being involved in several physiological events including blood pressure control and electrolyte balance. The AT1R is a member of the G protein coupled receptors (GPCR) family, classically known to couple G and engage β-arrestin recruitment. Both G protein and arrestin signaling pathways are involved in modulation of different downstream kinases.

Epilepsy Seizures in Spontaneously Hypertensive Rats After Acoustic Stimulation: Role of Renin-Angiotensin System.

Hypertension is a common comorbidity observed in individuals with epilepsy. Growing evidence suggests that lower blood pressure is associated with reduced frequency and severity of seizures. In this study, we sought to investigate whether the renin-angiotensin system (RAS), which is a critical regulator of blood pressure, is involved in the pathogenesis of audiogenic epilepsy-related seizures in a hypertensive rat model.

Beta-arrestin 2 mediates cardiac hypertrophy induced by thyroid hormones via AT1R.

We have previously reported that angiotensin II receptor type 1 (AT1R) contributes to the hypertrophic effects of thyroid hormones (TH) in cardiac cells. Even though evidence indicates crosstalks between TH and AT1R, the underlying mechanisms are poorly understood. Beta-arrestin (ARRB) signaling has been described as noncanonical signal transduction pathway that exerts important effects in the cardiovascular system through G-protein-coupled receptors, as AT1R.

Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H and H receptors.

Histamine acts through four different receptors (HR-HR), the HR and HR being the most explored in the last years as drug targets. The HR is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while HR blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human HR/HR ligands as potential drug candidates.

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II.

Nitrate and nitrite supplement deficient endogenous nitric oxide (NO) formation. While these anions may generate NO, recent studies have shown that circulating nitrite levels do not necessarily correlate with the antihypertensive effect of oral nitrite administration and that formation of nitrosylated species (RXNO) in the stomach is critically involved in this effect. This study examined the possibility that RXNO formed in the stomach after oral nitrite administration promotes target protein nitrosylation in the vasculature, inhibits vasoconstriction and the hypertensive responses to angiotensin II.

Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response.

Metastatic melanoma is an aggressive type of skin cancer leading half of the patients to death within 8-10 months after diagnosis. Kinins are peptides that interact with B1 and B2 receptors playing diverse biological roles. We investigated whether treatment with B1 receptor agonist, des-Arg-bradykinin (DABK), has effects in lung metastasis establishment after melanoma induction in mice.

Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D Receptor.

LASSBio-579, an -phenylpiperazine antipsychotic lead compound, has been previously reported as a D receptor (DR) ligand with antipsychotic-like activities in rodent models of schizophrenia. In order to better understand the molecular mechanism of action of LASSBio-579 and of its main metabolite, LQFM 037, we decided to address the hypothesis of functional selectivity at the DR. HEK-293T cells transiently coexpressing the human long isoform of D receptor (DLR) and bioluminescence resonance energy transfer (BRET)-based biosensors were used.

Activation of Toll-like receptor 2 induces B and B kinin receptors in human gingival fibroblasts and in mouse gingiva.

The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B and B receptor expression in human gingival fibroblasts and in mouse gingiva. Both P.

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors.

G protein-coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including protein kinase C (PKC), phospholipase C (PLC), p63RhoGEF, and Rho.

The binding of captopril to angiotensin I-converting enzyme triggers activation of signaling pathways.

Hypertension is a global health problem, and angiotensin I (ANG I)-converting enzyme (ACE) inhibitors are largely used to control this pathology. Recently, it has been shown that ACE can also act as a transducer signal molecule when its inhibitors or substrates bind to it. This new role of ACE could contribute to understanding some of the effects not explained by its catalytic activity only.

Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H and H Receptors with Anti-inflammatory Potential.

The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, HR and HR subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson's, and Alzheimer's diseases, which includes searches for dual acting HR/HR ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01 series) molecules were synthesized and evaluated as HR and HR ligands.

Ang-(1-7) is an endogenous β-arrestin-biased agonist of the AT receptor with protective action in cardiac hypertrophy.

The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT receptor (AT1R). Ang-(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by β-arrestin-biased agonists has been associated to cardioprotection.

Functional New World monkey oxytocin forms elicit an altered signaling profile and promotes parental care in rats.

The neurohormone oxytocin is a key player in the modulation of reproductive and social behavioral traits, such as parental care. Recently, a correlation between different forms of oxytocin and behavioral phenotypes has been described in the New World Monkeys (NWMs). Here, we demonstrate that, compared with the LeuOXT found in most placental mammals, the Cebidae ProOXT and ValProOXT taxon-specific variants act as equi-efficacious agonists for the G-dependent pathway but are weaker agonists for the β-arrestin engagement and subsequent endocytosis toward the oxytocin receptor (OXTR).

Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms.

Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms.

A Pluridimensional View of Biased Agonism.

When studying G protein-coupled receptor (GPCR) signaling and ligand-biased agonism, at least three dimensional spaces must be considered, as follows: 1) the distinct conformations that can be stabilized by different ligands promoting the engagement of different signaling effectors and accessory regulators; 2) the distinct subcellular trafficking that can be conferred by different ligands, which results in spatially distinct signals; and 3) the differential binding kinetics that maintain the receptor in specific conformation and/or subcellular localization for different periods of time, allowing for the engagement of distinct signaling effector subsets. These three pluridimensional aspects of signaling contribute to different faces of functional selectivity and provide a complex, interconnected way to define the signaling profile of each individual ligand acting at GPCRs. In this review, we discuss how each of these aspects may contribute to the diversity of signaling, but also how they shed light on the complexity of data analyses and interpretation.

Host kinin B1 receptor plays a protective role against melanoma progression.

Melanoma is a very aggressive tumor that arises from melanocytes. Late stage and widely spread diseases do not respond to standard therapeutic approaches. The kallikrein-kinin system (KKS) participates in biological processes such as vasodilatation, pain and inflammatory response.

Recent updates on GPCR biased agonism.

G protein-coupled receptors (GPCRs) are the most important targets for drug discovery and not surprisingly ∼40% of all drugs currently in the market act on these receptors. Currently, one of the most active areas in GPCRs signaling is biased agonism, a phenomenon that occurs when a given ligand is able to preferentially activate one (or some) of the possible signaling pathways. In this review, we highlight the most recent findings about biased agonism, including an extension of this concept to intracellular signaling, allosterism, strategies for assessment and interpretation, and perspectives of therapeutic applications for biased agonists.

A Novel Vasoactive Proline-Rich Oligopeptide from the Skin Secretion of the Frog Brachycephalus ephippium.

Proline-rich oligopeptides (PROs) are a large family which comprises the bradykinin-potentiating peptides (BPPs). They inhibit the activity of the angiotensin I-converting enzyme (ACE) and have a typical pyroglutamyl (Pyr)/proline-rich structure at the N- and C-terminus, respectively. Furthermore, PROs decrease blood pressure in animals.

Comparative analyses of downstream signal transduction targets modulated after activation of the AT1 receptor by two β-arrestin-biased agonists.

G protein-coupled receptors (GPCRs) are involved in essentially all physiological processes in mammals. The classical GPCR signal transduction mechanism occurs by coupling to G protein, but it has recently been demonstrated that interaction with β-arrestins leads to activation of pathways that are independent of the G protein pathway. Also, it has been reported that some ligands can preferentially activate one of these signaling pathways; being therefore called biased agonists for G protein or β-arrestin pathways.

Non-canonical signalling and roles of the vasoactive peptides angiotensins and kinins.

GPCRs (G-protein-coupled receptors) are among the most important targets for drug discovery due to their ubiquitous expression and participation in cellular events under both healthy and disease conditions. These receptors can be activated by a plethora of ligands, such as ions, odorants, small ligands and peptides, including angiotensins and kinins, which are vasoactive peptides that are classically involved in the pathophysiology of cardiovascular events. These peptides and their corresponding GPCRs have been reported to play roles in other systems and under pathophysiological conditions, such as cancer, central nervous system disorders, metabolic dysfunction and bone resorption.