α1D-Adrenergic Receptors

García‐Sáinz, J. Adolfo; Romero‐Ávila, M. Teresa; Medina, Luz del Carmen

doi:10.1016/b978-0-12-381298-8.00006-x

Cited by 14 publications

(12 citation statements)

References 46 publications

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“…Amino terminus (Δ1–79) (ΔN)-truncated mutant was used to improve receptor plasma membrane expression as it has been described (Pupo et al, 2003, Hague et al, 2004, García-Sáinz et al, 2010). In order to determine the role of the α 1D -adrenergic carboxyl terminus in signaling, a mutant with this deletion of the amino terminus (Δ1–79) (ΔN) and another with an additional carboxyl terminus deletion (Δ 441–572) (ΔNΔC) were expressed in Rat-1 cells (Rodríguez-Pérez et al, 2009) and changes in ERK phosphorylation and intracellular calcium were assessed.…”

Section: Resultsmentioning

confidence: 99%

Carboxyl terminus-truncated α1D-adrenoceptors inhibit the ERK pathway

Alfonzo-Méndez

Castillo‐Badillo

Romero‐Ávila

et al. 2016

Naunyn-Schmiedeberg's Arch Pharmacol

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Human α1D-adrenoceptors are G protein-coupled receptors that mediate adrenaline/noradrenaline actions. There is a growing interest in identifying regulatory domains in these receptors and determining how they function. In this work, we show that the absence of the human α1D-adrenoceptor carboxyl tail results in altered ERK (extracellular signal-regulated kinase) and p38 phosphorylation states. Amino terminus-truncated and both amino and carboxyl termini-truncated α1D-adrenoceptors were transfected into Rat-1, HEK293, and B103 cells, and changes in the phosphorylation state of extracellular signal-regulated kinase was assessed using biochemical and biophysical approaches. The phosphorylation state of other protein kinases (p38, MEK1, and Raf-1) was also studied. Noradrenaline-induced ERK phosphorylation in Rat-1 fibroblasts expressing amino termini-truncated α1D-adrenoceptors. However, in cells expressing receptors with both amino and carboxyl termini truncations, noradrenaline-induced activation was abrogated. Interestingly, ERK phosphorylation that normally occurs through activation of endogenous G protein-coupled receptors, EGF receptors, and protein kinase C, was also decreased, suggesting that downstream steps in the mitogen-activated protein kinase pathway were affected. A similar effect was observed in B103 cells but not in HEK 293 cells. Phosphorylation of Raf-1 and MEK1 was also diminished in Rat-1 fibroblasts expressing amino- and carboxyl-truncated α1D-adrenoceptors. Our data indicate that expression of carboxyl terminus-truncated α1D-adrenoceptors alters ERK and p38 phosphorylation state.

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Section: Resultsmentioning

confidence: 99%

Carboxyl terminus-truncated α1D-adrenoceptors inhibit the ERK pathway

Alfonzo-Méndez

Castillo‐Badillo

Romero‐Ávila

et al. 2016

Naunyn-Schmiedeberg's Arch Pharmacol

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“…[50] Constitutively active wild-type ADRA1D receptors have also been described in rat fibroblasts [51] and vasculature (i.e., aorta, mesenteric arteries) [52], and conformational changes in the receptor have been linked with not only receptor activity, but plasma membrane expression. [53] Taken altogether, these findings suggest a potential mechanistic explanation of ADRA1A’s persistent activity, although constitutive activity in α1A- and α1B-adrenoceptors has not yet been determined in physiological systems. [49] Ultimately, in contrast, the CYS isoform of the receptor, seen in T-allele carriers, appears to be appropriately sensitive to synaptic levels of NE, and with pharmacologic reduction in NE levels and attenuation of activity at the receptor, there is an observed reduction in cocaine use.…”

Section: Discussionmentioning

confidence: 98%

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals

Shorter

Nielsen

Hamon

et al. 2016

Pharmacogenetics and Genomics

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Objectives We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. Methods This study was a within-subject, double blind, placebo-controlled inpatient human laboratory evaluation of 65 non-treatment seeking, cocaine-dependent (DSM-IV) subjects, aged 18 to 55 years. Participants received both placebo (saline, IV) and cocaine (40mg, IV), and subjective responses were assessed 15 minutes prior to receiving an infusion and at 5-minute intervals for the subsequent 20 minutes. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. Results Thirty (46%) subjects were found to have the major allele CC genotype, and 35 (44%) carried at least one minor T allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype exhibited greater responses for ‘desire’ (p < 0.0001), ‘high’ (p < 0.0001), ‘any drug effect’ (p < 0.0001), ‘like cocaine” (p < 0.0001), and ‘likely to use cocaine if given access’ (p < 0.05) with experiment-wise significance. Conclusions This study indicates that ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine.

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“…The data are plotted as a normalized F/F 0 ratio, where F is the F 340 /F 380 ratio, and F 0 is the average F of the first 10 data points (50 s) before the addition of TG. Basal cytosolic Ca 2+ concentrations were calculated from F as previously described 53,54 using a Ca 2+ equilibrium dissociation constant of 225 nM. The Ca 2+ saturated and depleted conditions were calibrated by adding 0.2% (v/v) Triton X-100 and 10 mM EGTA to the cell suspensions, respectively.…”

Section: Generation and Recombinant Expression Of Full Luminal Domainmentioning

confidence: 99%

Synergistic stabilization by nitrosoglutathione-induced thiol modifications in the stromal interaction molecule-2 luminal domain suppresses basal and store operated calcium entry

Novello

Zhu

Zhang

et al. 2020

Sci Rep

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Stromal interaction molecule−1 and −2 (STIM1/2) are endoplasmic reticulum (ER) membrane-inserted calcium (Ca 2+) sensing proteins that, together with Orai1-composed Ca 2+ channels on the plasma membrane (PM), regulate intracellular Ca 2+ levels. Recent evidence suggests that S-nitrosylation of the luminal STIM1 Cys residues inhibits store operated Ca 2+ entry (SOCE). However, the effects of thiol modifications on STIM2 during nitrosative stress and their role in regulating basal Ca 2+ levels remain unknown. Here, we demonstrate that the nitric oxide (NO) donor nitrosoglutathione (GSNO) thermodynamically stabilizes the STIM2 Ca 2+ sensing region in a Cys-specific manner. We uncovered a remarkable synergism in this stabilization involving the three luminal Cys of STIM2, which is unique to this paralog. S-nitrosylation causes structural perturbations that converge on the face of the ef-hand and sterile α motif (EF-SAM) domain, implicated in unfolding-coupled activation. In HEK293T cells, enhanced free basal cytosolic ca 2+ and SOCE mediated by STIM2 overexpression could be attenuated by GSNO or mutation of the modifiable Cys located in the luminal domain. Collectively, we identify the Cys residues within the N-terminal region of STIM2 as modifiable targets during nitrosative stress that can profoundly and cooperatively affect basal Ca 2+ and Soce regulation. Stromal-interaction molecules (STIM)s are endoplasmic reticulum (ER) membrane-inserted calcium (Ca 2+) sensors that respond to fluctuations in luminal stored Ca 2+ levels 1,2. In Homo sapiens, two STIM homologs exist: stromal interaction molecule−1 (STIM1) and −2 (STIM2) 3. Upon ER luminal Ca 2+ store depletion, human STIM1 undergoes structural changes that promote oligomerization and translocation to ER-plasma membrane (PM) junctions 4-6. At these junctions, STIM1 interacts with Orai1 proteins, which are the pore-forming subunits of Ca 2+ release activated Ca 2+ (CRAC) channels 7-9. The direct interaction of STIM1 with Orai1 facilitates gating of the CRAC channels to induce the influx of extracellular Ca 2+ into the cytosol 10-12 , otherwise known as store operated Ca 2+ entry (SOCE) 13,14. The human STIM2 paralog similarly regulates SOCE; however, STIM2 is less efficient than STIM1 in this cellular process 15-18. Instead, STIM2 is more intimately involved in the regulation of basal Ca 2+ levels 15. Interestingly, in lower order eukaryotes such as Drosophila melanogaster and Caenorhabditis elegans, only one STIM gene product has been identified 3. The highly conserved EF-hand and sterile α-motif (EF-SAM) domains of STIMs are the core luminal protein machinery that sense ER Ca 2+ changes 17,19,20 , while the cytosolic STIM-Orai1-activating-region (SOAR) coiled-coils are the highly conserved cytosolic domains that couple to and open Orai1 channels 11,12. Compared

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α1D-Adrenergic Receptors

Cited by 14 publications

References 46 publications

Carboxyl terminus-truncated α1D-adrenoceptors inhibit the ERK pathway

Carboxyl terminus-truncated α1D-adrenoceptors inhibit the ERK pathway

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals

Synergistic stabilization by nitrosoglutathione-induced thiol modifications in the stromal interaction molecule-2 luminal domain suppresses basal and store operated calcium entry

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