Function of the Neuropeptide Head Activator for Early Neural and Neuroendocrine Development

Hampe, Wolfgang; Hermans‐Borgmeyer, Irm; Schaller, Heinz

doi:10.1007/978-3-540-49421-8_14

Cited by 9 publications

(3 citation statements)

References 39 publications

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“…To find a receptor for the neuropeptide head activator (Hampe et al, 1999), we constructed a novel phylogenetic tree that placed the orphan receptor GPR12 close to peptide and lipid receptors (Joost and Methner, 2002). We report in this paper that GPR12 is a high-affinity receptor for the lysophospholipid SPC and not for peptides.…”

Section: Introductionmentioning

confidence: 99%

Role of the G-Protein-Coupled Receptor GPR12 as High-Affinity Receptor for Sphingosylphosphorylcholine and Its Expression and Function in Brain Development

Ignatov¹,

Lintzel²,

et al. 2003

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Lysophospholipids are bioactive molecules influencing numerous cellular processes such as proliferation, differentiation, and motility. As extracellular ligands, they interact with specific members of the G-protein-coupled receptor family. We show in this paper that the lysophospholipid sphingosylphosphorylcholine is a high-affinity ligand for the orphan G-protein-coupled receptor GPR12. Heterologous expression of GPR12 in Chinese hamster ovary cells and in frog oocytes revealed a high-affinity interaction with sphingosylphosphorylcholine in the nanomolar range. Blockade of its action by pertussis toxin was taken as evidence that GPR12 is coupled to an inhibitory G-protein. In the adult mouse brain, GPR12 was expressed in the limbic system. During mouse embryonal development, GPR12 transcripts were detected in the CNS, especially in areas where neuronal differentiation occurs. Consistent with this we found that cultures of embryonal cerebral cortical neurons responded to sphingosylphosphorylcholine with an increase in synaptic contacts. The GPR12-expressing hippocampal cell line HT22 reacted to sphingosylphophorylcholine with an increase in cell proliferation and cell clustering. Other receptors known to interact at nanomolar concentrations with sphingosylphosphorycholine were expressed neither in the developing cerebral cortex nor in the HT22 cell line. We therefore hypothesize that sphingosylphosphorylcholine, most likely by interaction with GPR12, has positive effects on the differentiation and maturation of postmitotic neurons and that it may also influence the proliferation of neuronal precursor cells.

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Section: Introductionmentioning

confidence: 99%

Role of the G-Protein-Coupled Receptor GPR12 as High-Affinity Receptor for Sphingosylphosphorylcholine and Its Expression and Function in Brain Development

Ignatov¹,

Lintzel²,

et al. 2003

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“…Head activator is involved in head regeneration of coelenterates (18) and binds to the hydra orthologue of SorLA with nanomolar affinity (19 -21). In mammals, head activator mediates entry into mitosis and proliferation of neuronal and neuroendocrine precursor cells after binding to the VPS10 domain of SorLA (22).…”

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SorLA Signaling by Regulated Intramembrane Proteolysis

Böhm

Seibel

Henkel

et al. 2006

Journal of Biological Chemistry

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The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extracellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by ␥-secretase. Inhibition of ␥-secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the ␥-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA ␤-peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the ␥-secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by ␥-secretase.

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“…Another activator of this channel is the neuropeptide head activator (HA; Boels et al, 2001). HA stimulates neuronal and endocrine cell proliferation and requires the presence of a G‐protein–coupled receptor (GPCR) and Ca 2+ influx to stimulate mitosis (Hampe et al, 1999). Little remains known of the localization of HA receptors or TRPV2 in the brain of any species.…”

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Discrete expression of TRPV2 within the hypothalamo‐neurohypophysial system: Implications for regulatory activity within the hypothalamic‐pituitary‐adrenal axis

Wainwright

Rutter

Seabrook

et al. 2004

J of Comparative Neurology

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Transient receptor potential channel proteins (TRPs) constitute a steadily growing family of ion channels with a range of purported functions. It has been demonstrated that TRPV2 is activated by moderate thermal stimuli and, in the rat, is expressed in medium to large diameter dorsal root ganglion neurons. In this study, antisera specific for the human TRPV2 homologue were raised and characterized for immunohistochemical use. Subsequently, thorough investigation was made of the localization of this cation channel in the macaque primate brain. TRPV2-immunoreactive material was highly restrictively localized to hypothalamic paraventricular, suprachiasmatic, and supraoptic nuclei. Confocal double- and triple-labeling studies demonstrated that TRPV2 immunoreactivity is preferentially localized to oxytocinergic and vasopressinergic neurons. Few, if any, cells in these regions expressed TRPV2 immunoreactivity in the absence of oxytocin immunoreactivity or vasopressin immunoreactivity. Expression in the paraventricular and supraoptic nuclei suggests that TRPV2 is likely to play a fundamental role in mediating cation transport in neurohypophysial neurons. TRPV2 has been shown to be translocated upon cell activation and neurons expressing TRPV2 immunoreactivity in vivo are among those known to engage in sporadic, intense activity. Taken together, these data suggest that this channel may play a vital role in mediating physiological activities associated with oxytocin and vasopressin release such as parturition, lactation, and diuresis. These data may also implicate the involvement of TRPV2 in disorders of the hypothalamic-pituitary-adrenal axis, including anxiety, depression, hypertension, and preterm labor.

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Function of the Neuropeptide Head Activator for Early Neural and Neuroendocrine Development

Cited by 9 publications

References 39 publications

Role of the G-Protein-Coupled Receptor GPR12 as High-Affinity Receptor for Sphingosylphosphorylcholine and Its Expression and Function in Brain Development

Role of the G-Protein-Coupled Receptor GPR12 as High-Affinity Receptor for Sphingosylphosphorylcholine and Its Expression and Function in Brain Development

SorLA Signaling by Regulated Intramembrane Proteolysis

Discrete expression of TRPV2 within the hypothalamo‐neurohypophysial system: Implications for regulatory activity within the hypothalamic‐pituitary‐adrenal axis

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