G

Dautzenberg, Norbert

doi:10.1007/978-3-322-86986-9_7

Cited by 5 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many studies using chimeric or mutant receptors have shown that the extracellular domains contribute to the binding and ligand selectivity [29][30][31] and further, that the ECD1 constitutes a major peptide-binding domain. 30,[32][33][34][35][36] The juxtamembrane receptor domain, that is, the receptor excluding the ECD1, also binds peptide ligands, albeit with significantly lower affinity. 35 The data from the constitutively active tethered-ligand receptor show that the juxtamembrane domain is involved in transducing the signaling response.…”

Section: Crf Receptorsmentioning

confidence: 99%

The Three‐Dimensional Structure of the N‐Terminal Domain of Corticotropin‐Releasing Factor Receptors

Perrin

Grace

Riek

et al. 2006

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

The corticotropin-releasing factor (CRF) receptors, CRF-R1 and CRF-R2, belong to the B1 subfamily of G protein-coupled Receptors (GPCRs), including receptors for secretin, growth hormone-releasing hormone (GHRH), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin, parathyroid hormone (PTH), glucagon, and glucagon-like peptide-1 (GLP-1). The peptide ligand family comprises CRF, Ucn 1, 2, and 3. CRF plays the major role in integrating the response to stress. Additionally, the ligands exhibit many effects on muscle, pancreas, heart, and the GI, reproductive, and immune systems. CRF-R1 has higher affinity for CRF than does CRF-R2 while both receptors bind Ucn 1 equally. CRF-R2 shows specificity for Ucns 2 and 3. A major binding domain of the CRFRs is the N terminus/first extracellular domain (ECD1). Soluble proteins corresponding to the ECD1s of each receptor bind CRF ligands with nanomolar affinities. Our three-dimensional (3D) nuclear magnetic resonance (NMR) structure of a soluble protein corresponding to the ECD1 of CRF-R2beta (1) identified its structural fold as a Sushi domain/short consensus repeat (SCR), stabilized by three disulfide bridges, two tryptophan residues, and an internal salt bridge (Asp65-Arg101). Disruption of the bridge by D65A mutation abrogates ligand recognition and results in loss of the well-defined disulfide pattern and Sushi domain structure. NMR analysis of the ECD1 in complex with astressin identified key amino acids involved in ligand recognition. Mutation of some of these residues in the full-length receptor reduces its affinity for CRF ligands. A structure-based sequence comparison shows conservation of key amino acids in all the B1 subfamily receptors, suggesting a corresponding conservation of a Sushi domain structural fold of their ECD1s.

show abstract

Section: Crf Receptorsmentioning

confidence: 99%

The Three‐Dimensional Structure of the N‐Terminal Domain of Corticotropin‐Releasing Factor Receptors

Perrin

Grace

Riek

et al. 2006

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

show abstract

“…There are many PAC1 splice variants, including N-terminal deletions and intracellular loop insertions; these modify the peptide binding and signalling properties of the receptor (Spongier et al, 1993;Blechman and Levkowitz, 2013). The most commonly studied variant, PAC1n, as defined by Dautzenberg et al, 1999, contains the full N-terminal domain and lacks insertions into the intracellular loops (Spongier et al, 1993;Pisegna and Wank, 1996;Dautzenberg et al, 1999;Furness et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells

Walker

Sundrum

Hay

2014

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose A major challenge in the development of new medicines targeting GPCRs is the ability to quantify drug action in physiologically relevant models. Primary cell models that closely resemble the clinically relevant in vivo site of drug action are important translational tools in drug development. However, pharmacological studies in these models are generally very limited due to the methodology used. Experimental Approach We used a neuropeptide system to demonstrate the applicability of using highly sensitive signalling assays in primary cells. We quantified the action of pituitary adenylate cyclase‐activating peptide (PACAP)‐38, PACAP‐27 and vasoactive intestinal polypeptide in primary cultures of neurons and glia derived from rat trigeminal ganglia (TG), comparing our observations to transfected cells. Key Results PACAP‐responsive receptors in rat trigeminal neurons, glia and transfected PAC1n receptors were pharmacologically distinct. PACAP‐38, but not PACAP‐27, activated ERK in glia, while both forms stimulated cellular cAMP production. PACAP(6–38) also displayed cell‐type‐dependent, agonist‐specific, antagonism. Conclusions and Implications The complexity of PACAP pharmacology in the TG may help to direct, more effectively, the development of disease treatments targeting the PACAP receptor. We suggest that these methodologies are broadly applicable to other primary cell types of human or animal origin, and that our approach may allow more thorough characterization of ligand properties in physiologically relevant cell types.

show abstract

“…Both PACAP isoforms belong to the vasoactive intestinal polypeptide (VIP) family. Two PACAP receptors with similar affinity for VIP and PACAP are VPAC1 and VPAC2, whereas the PAC1 receptor prefers PACAP exclusively (Dautzenberg et al, 1999). By alternative splicing of the PAC1 gene, six receptor isoforms are generated with or without the inclusion of three 28-amino-acid sequences/cassettes (HIP, HOP-1 and/ or HOP-2) in the third intracellular loop; the short form includes no cassettes (Spengler et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Receptors for NPY and PACAP differ in expression and activity during adipogenesis in the murine 3T3‐L1 fibroblast cell line

Gericke¹,

Kosacka²,

Koch³

et al. 2009

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: Neuropeptides are involved in the regulation of food intake in the central nervous system, but they might also act on peripheral fat tissue via neuropeptide receptors. Experimental approach: We investigated the receptor expression and activity of pituitary adenylate cyclase-activating polypeptide (PACAP) and of neuropeptide Y at the mRNA and protein levels in the 3T3-L1 fibroblast line during differentiation into adipocytes. Intracellular calcium concentration was measured by calcium imaging. Key results: The PACAP receptors PAC1 and VPAC2 as well as the neuropeptide Y1 receptor were expressed at the mRNA level in fibroblasts, pre-adipocytes and adipocytes. The mRNA profile of the PAC1 receptor isoforms showed the HOP sequence, whereas the HIP-isoform was present in subconfluent 3T3-L1 fibroblasts only. At the protein level, the mature 3T3-L1 adipocytes produced the PAC1 and Y1 receptors; only the PAC1 receptor showed carbohydrate residues. Both neuropeptides induced an increase of intracellular calcium in mature adipocytes, which was absent in the precursor cells. These changes in calcium were mediated by Y1 and PAC1 receptors as demonstrated by the effects of specific receptor agonists and antagonists. Conclusions and implications:As the PAC1-HOP receptor variant seems to be responsible for PACAP-mediated calcium influx in many cell types, the HOP sequence might also mediate the increase in intracellular calcium in adipocytes. Because a high intracellular calcium level is associated with lipogenesis, peptidergic innervation of adipose tissue might be involved in stress-induced obesity.

show abstract

G

Cited by 5 publications

References 0 publications

The Three‐Dimensional Structure of the N‐Terminal Domain of Corticotropin‐Releasing Factor Receptors

The Three‐Dimensional Structure of the N‐Terminal Domain of Corticotropin‐Releasing Factor Receptors

PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells

Receptors for NPY and PACAP differ in expression and activity during adipogenesis in the murine 3T3‐L1 fibroblast cell line

Contact Info

Product

Resources

About