-
International Journal of Molecular... Jan 2021Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its...
Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its constituent receptor units. Detection of these complexes and monitoring their pharmacology is crucial for understanding how receptors function. The Receptor-Heteromer Investigation Technology (Receptor-HIT) utilizes ligand-dependent modulation of interactions between receptors and specific biomolecules for the detection and profiling of heteromer complexes. Previously, the interacting biomolecules used in Receptor-HIT assays have been intracellular proteins, however in this study we have for the first time used bioluminescence resonance energy transfer (BRET) with fluorescently-labeled ligands to investigate heteromerization of receptors on the cell surface. Using the Receptor-HIT ligand binding assay with NanoBRET, we have successfully investigated heteromers between the angiotensin II type 1 (AT) receptor and the β adrenergic receptor (AT-βAR heteromer), as well as between the AT and angiotensin II type 2 receptor (AT-AT heteromer).
Topics: Binding, Competitive; Bioluminescence Resonance Energy Transfer Techniques; Boron Compounds; Cell Membrane; Cyclic AMP; Fluorescence Resonance Energy Transfer; HEK293 Cells; Humans; Kinetics; Ligands; Nanotechnology; Protein Binding; Protein Multimerization; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Adrenergic, beta-2; Receptors, Angiotensin; Signal Transduction
PubMed: 33499147
DOI: 10.3390/ijms22031082 -
BMC Neuroscience Dec 2008Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of... (Review)
Review
Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out.
Topics: Angiotensin II; Animals; Cognition; Cystinyl Aminopeptidase; Humans; Memory; Receptors, Angiotensin; Renin-Angiotensin System
PubMed: 19090988
DOI: 10.1186/1471-2202-9-S2-S15 -
Neurochemistry International Sep 2022We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic...
We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic Wistar rats. In this study, we examined the expression of AT2R in type 2 diabetic Goto-Kakizaki (GK) rats and control Wistars after stroke. We also tested the contribution of the contralesional AT2R in recovery after stroke through a specific knockdown of the AT2R in this hemisphere only. Two experiments were conducted. In the first experiment, GK rats were subjected to middle cerebral artery occlusion (MCAO) and treated with the angiotensin II receptor type 1 receptor (AT1R) blocker candesartan or saline at reperfusion. Stroke outcomes, as well as AT2R expression, were examined and compared to control Wistars at 24 h. In the second experiment, localized AT2R knockdown was achieved through intrastriatal injection of short hairpin RNA (shRNA) lentiviral particles or non-targeting control into the left-brain hemisphere of Wistar rats. After 14 days, rats were subjected to right MCAO and treated with the AT2R agonist, Compound 21 (C21), or saline for 7 days. Behavioral outcomes were assessed for up to 10 days. In the first experiment, stroke reduced the expression of AT2R in GK rats. Candesartan treatment failed to improve the neurobehavioral outcomes, preserve vascular integrity or reduce oxidative/nitrative stress or apoptotic markers at 24 h post stroke in these animals. In the second experiment, contralesional AT2R knockdown reduced the C21-mediated functional recovery after stroke. In conclusion, contralesional AT2R upregulation after stroke is blunted in diabetic rats which show reduced sensitivity to post-stroke candesartan treatment. Contralesional AT2R could be involved in C21-mediated functional recovery after stroke.
Topics: Animals; Diabetes Mellitus, Experimental; Imidazoles; Infarction, Middle Cerebral Artery; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Stroke; Sulfonamides; Thiophenes
PubMed: 35688299
DOI: 10.1016/j.neuint.2022.105375 -
International Journal of Molecular... Jun 2022This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT receptors (ATRs) by angiotensin II (Ang... (Review)
Review
This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT receptors (ATRs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB receptors (CBRs), modify the response to ATR stimulation. CBR blockade may enhance ATR-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CBRs and ATRs induces opposite or the same effects. Second, CBR blockade may diminish ATR levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II-AT receptor system or angiotensin 1-7-Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of ATR-CBR heteromerization. As a therapeutic consequence, CBR antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.
Topics: Angiotensin II; COVID-19; Cannabinoids; Endocannabinoids; Humans; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Cannabinoid; Renin; Renin-Angiotensin System
PubMed: 35683028
DOI: 10.3390/ijms23116350 -
Molecules (Basel, Switzerland) Oct 2021The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of... (Review)
Review
The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.
Topics: Analgesics; Analgesics, Opioid; Animals; Chronic Pain; Humans; Neuralgia; Nociception; Pain Management; Proto-Oncogene Mas; Receptors, Angiotensin; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 34684749
DOI: 10.3390/molecules26206168 -
Neurotherapeutics : the Journal of the... Apr 2021The renin-angiotensin system (RAS) not only plays an important role in controlling blood pressure but also participates in almost every process to maintain homeostasis...
Novel Interactions Involving the Mas Receptor Show Potential of the Renin-Angiotensin system in the Regulation of Microglia Activation: Altered Expression in Parkinsonism and Dyskinesia.
The renin-angiotensin system (RAS) not only plays an important role in controlling blood pressure but also participates in almost every process to maintain homeostasis in mammals. Interest has recently increased because SARS viruses use one RAS component (ACE2) as a target-cell receptor. The occurrence of RAS in the basal ganglia suggests that the system may be targeted to improve the therapy of neurodegenerative diseases. RAS-related data led to the hypothesis that RAS receptors may interact with each other. The aim of this paper was to find heteromers formed by Mas and angiotensin receptors and to address their functionality in neurons and microglia. Novel interactions were discovered by using resonance energy transfer techniques. The functionality of individual and interacting receptors was assayed by measuring levels of the second messengers cAMP and Ca in transfected human embryonic kidney cells (HEK-293T) and primary cultures of striatal cells. Receptor complex expression was assayed by in situ proximity ligation assay. Functionality and expression were assayed in parallel in primary cultures of microglia treated or not with lipopolysaccharide and interferon-γ (IFN-γ). The proximity ligation assay was used to assess heteromer expression in parkinsonian and dyskinetic conditions. Complexes formed by Mas and the angiotensin AT or AT receptors were identified in both a heterologous expression system and in neural primary cultures. In the heterologous system, we showed that the three receptors-MasR, ATR, and ATR-can interact to form heterotrimers. The expression of receptor dimers (ATR-MasR or ATR-MasR) was higher in microglia than in neurons and was differentially affected upon microglial activation with lipopolysaccharide and IFN-γ. In all cases, agonist-induced signaling was reduced upon coactivation, and in some cases just by coexpression. Also, the blockade of signaling of two receptors in a complex by the action of a given (selective) receptor antagonist (cross-antagonism) was often observed. Differential expression of the complexes was observed in the striatum under parkinsonian conditions and especially in animals rendered dyskinetic by levodopa treatment. The negative modulation of calcium mobilization (mediated by ATR activation), the multiplicity of possibilities on RAS affecting the MAPK pathway, and the disbalanced expression of heteromers in dyskinesia yield new insight into the operation of the RAS system, how it becomes unbalanced, and how a disbalanced RAS can be rebalanced. Furthermore, RAS components in activated microglia warrant attention in drug-development approaches to address neurodegeneration.
Topics: Angiotensin II; Animals; Corpus Striatum; Dyskinesia, Drug-Induced; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Microglia; Oxidopamine; Parkinsonian Disorders; Proto-Oncogene Mas; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System
PubMed: 33474655
DOI: 10.1007/s13311-020-00986-4 -
Biochemical Pharmacology Nov 2023Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease whereby excessive deposition of extracellular matrix proteins (ECM) ultimately leads to... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease whereby excessive deposition of extracellular matrix proteins (ECM) ultimately leads to respiratory failure. While there have been advances in pharmacotherapies for pulmonary fibrosis, IPF remains an incurable and irreversible disease. There remains an unmet clinical need for treatments that reverse fibrosis, or at the very least have a more tolerable side effect profile than currently available treatments. Transforming growth factor β1(TGFβ1) is considered the main driver of fibrosis in IPF. However, as our understanding of the role of the pulmonary renin-angiotensin system (PRAS) in the pathogenesis of IPF increases, it is becoming clear that targeting angiotensin receptors represents a potential novel treatment strategy for IPF - in particular, via activation of the anti-fibrotic angiotensin type 2 receptor (ATR). This review describes the current understanding of the pathophysiology of IPF and the mediators implicated in its pathogenesis; focusing on TGFβ1, angiotensin II and related peptides in the PRAS and their contribution to fibrotic processes in the lung. Preclinical and clinical assessment of currently available ATR agonists and the development of novel, highly selective ligands for this receptor will also be described, with a focus on compound 21, currently in clinical trials for IPF. Collectively, this review provides evidence of the potential of ATR as a novel therapeutic target for IPF.
Topics: Humans; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Fibrosis; Angiotensin II; Receptors, Angiotensin
PubMed: 37778444
DOI: 10.1016/j.bcp.2023.115839 -
Life Sciences Nov 2012Angiotensin II (Ang II) interacts with AT(1) and AT(2) receptors and, in some vertebrates, with an Ang II binding site showing low affinity for AT(1) and AT(2) receptor... (Comparative Study)
Comparative Study
AIM
Angiotensin II (Ang II) interacts with AT(1) and AT(2) receptors and, in some vertebrates, with an Ang II binding site showing low affinity for AT(1) and AT(2) receptor antagonists. This study was carried out to characterize the Ang II receptor, and the presence of an angiotensin-converting enzyme (ACE) in the aorta of the Bothrops jararaca snake.
MAIN METHOD
Contraction induced by Ang I or II in aortic ring from the snake was evaluated in the absence or in the presence of ACE-blocker or Ang II antagonists.
KEY FINDINGS
Ang II analogs, modified at positions 1 and 5, induced vasoconstriction with differences in their potencies. The relative rank order was: [Asp(1), Val(5)] Ang II=[Asp(1), Ile(5)] Ang II>>>[Asn(1), Val(5)] Ang II. ACE-like activity was detected, as well as an Ang II receptor with low affinity for AT(1) and AT(2) selective receptor antagonists (pK(B) values of 5.62±0.23 and 5.08±0.25). A disulfide reducing agent almost abolished the Ang II effect, while an alpha adrenoceptor antagonist, or removing the endothelium, did not modify the Ang II effect. These results indicate that the B. jararaca aorta has an Ang II receptor pharmacologically distinct from AT(1) and AT(2) receptors, and the vasoconstrictor effect observed is independent of catecholamine or endothelium modulation. ACE and the AT receptor in the aorta of B. jararaca may be part of a tissue renin-angiotensin system.
SIGNIFICANCE
The data contribute to the knowledge of the renin-angiotensin system in vertebrate species, and provide insight into the understanding of snake Ang II receptor characteristics and diversity.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Bothrops; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Vasoconstriction
PubMed: 23000029
DOI: 10.1016/j.lfs.2012.09.006 -
Journal of the American Heart... Jul 2020
Topics: Angiotensins; Heart Failure; Humans; Hypertension, Pulmonary; Neprilysin; Receptors, Angiotensin; Ventricular Remodeling
PubMed: 32552147
DOI: 10.1161/JAHA.120.017292 -
Kidney International Jun 2002
Topics: Angiotensin II; Animals; NF-kappa B; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 12028470
DOI: 10.1046/j.1523-1755.2002.00388.x