Garrett Enten Ph. D.

@article{pmid36925091,

title = {α_{1}-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α_{1B/D}-adrenoceptors via interference with heteromer formation},

author = {Xianlong Gao and Garrett A Enten and Michelle Y McGee and McWayne Weche and Matthias Majetschak},

url = {https://pubmed.ncbi.nlm.nih.gov/36925091/},

doi = {10.1016/j.phrs.2023.106730},

issn = {1096-1186},

year  = {2023},

date = {2023-04-01},

urldate = {2023-04-01},

journal = {Pharmacol Res},

volume = {190},

pages = {106730},

abstract = { We reported previously that α_{1}-adrenoceptor (α_{1}-AR) ligands inhibit chemokine receptor (CR) heteromerization partners of α_{1B/D}-AR. The underlying mechanisms are unknown and in vivo evidence for such effects is missing. Utilizing CCR2 and α_{1B}-AR as prototypical partners, we observed in recombinant systems and THP-1 cells that α_{1B}-AR enhanced whereas its absence inhibited Gαi signaling of CCR2. Phenylephrine and phentolamine reduced the CCR2:α_{1B}-AR heteromerization propensity and inhibited Gαi signaling of CCR2. Phenylephrine cross-recruited β-arrestin-2 to CCR2, and reduced expression of α_{1B/D}-AR, CR partners (CCR1/2, CXCR4) and corresponding heteromers. Phentolamine reduced CR:α_{1B/D}-AR heteromers without affecting β-arrestin-2 recruitment or receptor expression. Phenylephrine/phentolamine prevented leukocyte infiltration mediated via CR heteromerization partners in a murine air pouch model. Our findings document that α_{1}-AR ligands inhibit leukocyte migration mediated by CR heteromerization partners in vivo and suggest interference with α_{1B}-AR:CR heteromerization as a mechanism by which CR partners are inhibited. These findings provide new insights into the pharmacology of GPCR heteromers and indicate that an agonist and antagonist at one GPCR can act as antagonists at heteromerization partners of their target receptors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35537053,

title = {α_{1B/D}-adrenoceptors regulate chemokine receptor-mediated leukocyte migration via formation of heteromeric receptor complexes},

author = {Garrett A Enten and Xianlong Gao and Hannah R Strzelinski and McWayne Weche and Stephen B Liggett and Matthias Majetschak},

url = {https://pubmed.ncbi.nlm.nih.gov/35537053/},

doi = {10.1073/pnas.2123511119},

issn = {1091-6490},

year  = {2022},

date = {2022-05-01},

urldate = {2022-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {119},

number = {20},

pages = {e2123511119},

abstract = {   It is known that catecholamines regulate innate immune functions. The underlying mechanisms, however, are not well understood. Here we show that at least 20 members of the human chemokine receptor (CR) family heteromerize with one or more members of the α1-adrenergic receptor (AR) family in recombinant systems and that such heteromeric complexes are detectable in human monocytes and the monocytic leukemia cell line THP-1. Ligand binding to α1-ARs inhibited migration toward agonists of the CR heteromerization partners of α1B/D-ARs with high potency and 50 to 77% efficacy but did not affect migration induced by a noninteracting CR. Incomplete siRNA knockdown of α1B/D-ARs in THP-1 cells partially inhibited migration toward agonists of their CR heteromerization partners. Complete α1B-AR knockout via CRISPR-Cas9 gene editing in THP-1 cells (THP-1_ADRA1BKO) resulted in 82% reduction of α1D-AR expression and did not affect CR expression. Migration of THP-1_ADRA1BKO cells toward agonists of CR heteromerization partners of α1B/D-ARs was reduced by 82 to 95%. Our findings indicate that CR:α1B/D-AR heteromers are essential for normal function of CR heteromerization partners, provide a mechanism underlying neuroendocrine control of leukocyte trafficking, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34144642,

title = {Chemokine receptor antagonists with α_{1}-adrenergic receptor blocker activity},

author = {Anthony J DeSantis and Garrett A Enten and Xianlong Gao and Matthias Majetschak},

url = {https://pubmed.ncbi.nlm.nih.gov/34144642/},

doi = {10.1515/jbcpp-2020-0523},

issn = {2191-0286},

year  = {2021},

date = {2021-06-01},

urldate = {2021-06-01},

journal = {J Basic Clin Physiol Pharmacol},

volume = {33},

number = {4},

pages = {519--523},

abstract = {Results:

Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α_{1b}-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α_{1}-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α_{1}-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.



Methods:

The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α_{1b}-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α_{1}-adrenoceptor antagonist prazosin was used as control.



Results:

Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α_{1b}-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α_{1}-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α_{1}-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.



Conclusions:

Our data suggest that CCR antagonists should be screened for cross-reactivity with α_{1}-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32647374,

title = {Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia-reperfusion injury and hemorrhage},

author = {Favin S Babu and Xiaomei Liang and Garrett A Enten and Anthony J DeSantis and Brian F Volkman and Xianlong Gao and Matthias Majetschak},

url = {https://pubmed.ncbi.nlm.nih.gov/32647374/},

doi = {10.1038/s41598-020-68425-0},

issn = {2045-2322},

year  = {2020},

date = {2020-07-01},

urldate = {2020-07-01},

journal = {Sci Rep},

volume = {10},

number = {1},

pages = {11359},

abstract = {We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO_{2}/FiO_{2}-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL12_{1}, CXCL2_{2}, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL12_{1} and CXCL12_{2} prevented ARDS development. Potencies of CXCL12/CXCL12_{1}/CXCL12_{2} were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL12_{1} > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}