PAC 1 Receptor Activation by PACAP-38 Mediates Ca 2؉ Release from a cAMP-dependent Pool in Human Fetal Adrenal Gland Chromaffin Cells* Downloaded from

International audiencePrevious studies have shown that human fetal adre-nal gland from 17-to 20-week-old fetuses expressed pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, which were localized on chromaf-fin cells. The aim of the present study was to identify PACAP receptor isoforms and to determine whether PACAP can affect intracellular calcium concentration ([Ca 2؉ ] i) and catecholamine secretion. Using primary cultures and specific stimulation of chromaffin cells, we demonstrate that PACAP-38 induced an increase in [Ca 2؉ ] i that was blocked by PACAP (6-38), was independent of external Ca 2؉ , and originated from thapsi-gargin-insensitive internal stores. The PACAP-triggered Ca 2؉ increase was not affected by inhibition of PLC␤ (preincubation with U-73122) or by pretreatment of cells with Xestospongin C, indicating that the inosi-tol 1,4,5-triphosphate-sensitive stores were not mobilized. However, forskolin (FSK), which raises cytosolic cAMP, induced an increase in Ca 2؉ similar to that recorded with PACAP-38. Blockage of PKA by H-89 or (R p)-cAMPS suppressed both PACAP-38 and FSK calcium responses. The effect of PACAP-38 was also abolished by emptying the caffeine/ryanodine-sensitive Ca 2؉ stores. Furthermore, treatment of cells with or-thovanadate (100 M) impaired Ca 2؉ reloading of PACAP-sensitive stores indicating that PACAP-38 can mobilize Ca 2؉ from secretory vesicles. Moreover, PACAP induced catecholamine secretion by chromaf-fin cells. It is concluded that PACAP-38, through the PAC 1 receptor, acts as a neurotransmitter in human fetal chromaffin cells inducing catecholamine secretion , through nonclassical, recently described, ryano-dine/caffeine-sensitive pools, involving a cAMP-and PKA-dependent phosphorylation mechanism. Pituitary adenylate cyclase-activating polypeptide is a 38-residue ␣-amidated neuropeptide (PACAP-38) 1 originally isolated from the ovine hypothalamus for its ability to stimulate cAMP formation in rat anterior pituitary cells. Processing of PACAP-38 can generate a 27-amino acid amidated peptide (PACAP-27) that exhibits 68% sequence identity with vasoac-tive intestinal polypeptide (VIP), thus identifying PACAP as a member of the VIP/secretin/glucagon superfamily of regulatory peptides (1, 2). The effects of PACAP are mediated through interaction with two types of high affinity receptors: type I receptors are selectively activated by PACAP, whereas type II receptors bind PACAP and VIP with similar affinity (3). Three isoforms of PACAP receptors have now been cloned and designated as PACAP-specific receptor I (PAC 1-R) (4, 5) and VIP/PACAP mutual receptors 1 and 2 (VPAC 1-R and VPAC 2-R) (6, 7). Both PAC 1-R (type 1 receptors) and VPAC 1-R/VPAC 2-R (type 2 receptors) belong to the seven-transmembrane domain, G-protein coupled receptor family, and are all positively coupled to adenylyl cyclase (2). Eight isoforms of PAC 1-R, resulting from alternative splicing, have been characterized to date. These variants display differential signal transduction properties with regard to adenylyl cyclase and phospholipase C (PLC) stimulation (1, 2). In addition to these classical signaling pathways , PACAP has been found to stimulate a Ca 2ϩ-calmodulin nitric oxide synthase (8) and mitogen-activated protein kinase activity (9). These various transduction mechanisms are involved in the neurotrophic activities exerted by PACAP (i.e. inhibition of apoptosis and stimulation of neurite outgrowth) during development (9-11). PACAP and its receptors are actively expressed in the adre-nal medulla (12-14). In particular, we have previously demonstrated the occurrence of PACAP-38 (15) and PACAP binding sites (16) in chromaffin cells from 16-to 20-week-old fetal human adrenal glands. Activation of these receptors by PACAP-38 causes stimulation of cAMP production and induces a modest increase in inositol 1,4,5-triphosphate (IP 3) formation (16), suggesting a role for the neuropeptide in the developin

VIP and PACAP receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [64, 65]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [29]. PG 99-465 [115] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [35]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [116]. Two deletion variants of maxadilan, M65 [180] and Max.d.4 [117] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised

VIP and PACAP receptors in GtoPdb v.2023.1

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [65, 66]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [30]. PG 99-465 [117] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [36]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [118]. Two deletion variants of maxadilan, M65 [183] and Max.d.4 [119] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised

Melanotrope Secretory Cycle is Regulated by Physiological Inputs via the Hypothalamus

Previously, it has been shown that background color conditions regulate the overall activity of the frog intermediate lobe by varying the proportions of the two subtypes of melanotropes existing in the gland, the highly active or secretory melanotropes and hormone-storage melanotropes, depending on melanocyte-stimulating hormone ( -MSH) requirements. However, the factors and mechanisms underlying these background-induced changes are still unknown. In the present study, we investigated whether hypothalamic factors known to regulate melanotrope cell function can induce changes in vitro similar to those caused by background adaptation in vivo. We found that the inhibitors apomorphine (a dopamine receptor agonist) and NPY decreased the number of active melanotropes and increased simultaneously that of storage melanotropes. On the other hand, the stimulator TRH increased the number of active cells and concomitantly reduced that of storage cells. Inasmuch as none of these treatments modified the apoptotic and proliferation rates in melanotrope cells, it appears that these hypothalamic factors caused actual interconversions of cells from a subpopulation to its counterpart. When taken together, these findings suggest that the hypothalamus would control melanotrope activity not only through short-term regulation of hormone synthesis and release, but also through a long-term regulation of the secretory phenotype of these cells whereby the activity of the intermediate lobe would be adjusted to fulfill the hormonal requirements imposed by background conditions

Neurones à kisspeptine et oestrogènes. Etude chez le poisson zèbre et le loup de mer. Kisspeptin neurones and their relationships with estrogens. Study in two fish species the zebrafish and the sea bass.

Supported by EU Project LIFECYCLE (FP7-222719-1) to OK and SZ, NEMO project to OK and ACOM/2010/086-GV. SE was supported by a JAE-Predoc (CSIC, Spain).Peer Reviewe

Urotensin receptor in GtoPdb v.2023.1

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 94]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 93]. Several structural forms of U-II exist in fish and amphibians [94]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [94]. The urotensinergic system displays an unprecedented repertoire of four or five ancient UT in some vertebrate lineages and five U-II family peptides in teleost fish [91]

Urotensin receptor in GtoPdb v.2021.3

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 93]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 92]. Several structural forms of U-II exist in fish and amphibians [93]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [93]

Urotensin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 89]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 88]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [20, 62, 68, 70]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [53, 11]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [83]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [89]

QRFP receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The human gene encoding the QRFP receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the QRFP receptor [16]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [15]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y2 (37%) and galanin Gal1 (35%) receptors