Demonstration of parathyroid hormone-related protein in meninges and its receptor in astrocytes: evidence for a paracrine meningo-astrocytic loop

Struckhoff, Gernot; Turzynski, Andreas

doi:10.1016/0006-8993(95)00088-8

Cited by 27 publications

(12 citation statements)

References 44 publications

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“…The addition of PTHrP directly to the culture medium stimulated cAMP in a dose-dependent manner, as expected for the adenylate cyclase-coupled PTH/PTHrP receptor. The V 0.5 of ϳ16 nM, which we observed for PTHrP-(1-36) is similar to the ϳ30 nM previously reported using a cortical astrocyte culture model (31). These affinities are much lower than the ϳ0.5 nM previously reported for this receptor in renal membranes (32) and likely reflect the differences in peptide concentrations to which each receptor is exposed in vivo (33); the cerebellar receptor is bathed in high concentrations of PTHrP released locally by adjacent cells, whereas the renal receptor responds to nanomolar concentrations of the circulating hormone, PTH.…”

Section: Discussionsupporting

confidence: 73%

“…Prior in situ hybridization studies suggested these same conclusions in vivo (12,13). Direct study of primary cultures of cortical type I astrocytes by others has also shown that glia do not make PTHrP (31).…”

Section: Discussionmentioning

confidence: 49%

“…Many of the neurons that express the PTHrP gene are known to be rich in L-VSCCs, excitatory amino acid receptors, and Na ϩ ,K ϩ -ATPase (13). PTH/PTHrP receptor mRNA has also been reported by two groups in cultured cortical type I astrocytes (31,34), but it did not seem to be present in cerebellar glia populating neuron-depleted cultures.…”

Section: Discussionmentioning

confidence: 96%

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Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Holt¹,

Broadus

Brines

1996

Journal of Biological Chemistry

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Parathyroid hormone (PTH)1 -related peptide (PTHrP) was initially recognized as a tumor product that is responsible for most instances of the syndrome of humoral hypercalcemia of malignancy, a common metabolic complication of cancer (1-3). In this circumstance, PTHrP is elaborated by tumors in a sufficient quantity to cross-react with the classical PTH receptor in bone and kidney, resulting in the prototypical biochemical and clinical features of humoral hypercalcemia of malignancy. It is now known that the PTH and PTHrP genes arose by duplication and are two members of a small gene family (3). What remains from this common origin is a similar intron/exon organization and a short stretch of highly homologous sequence at the N terminus of each mature peptide. These N-terminal sequences appear to share a single G protein-coupled receptor, the PTH/PTHrP receptor (4). This is an interesting and un-

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 49%

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Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Holt¹,

Broadus

Brines

1996

Journal of Biological Chemistry

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“…In the rat, PTHrP has also been detected in the meninges but not in astrocytes that have PTH/PTHrP receptors (Struckhoff and Turzynski 1995). We evaluated the presence of PTHrP in human astrocytomas, using immunohistochemistry and Western immunoblot analysis.…”

mentioning

confidence: 99%

“…In the rat, the PTH/PTHrP receptor, but not PTHrP, is highly expressed in cortical astrocytes, in which PTHrP[1-34] induces a process-bearing cell morphology and increases cellular glial fibrillary acidic protein (Struckhoff and Turzynski 1995). In these cells, PTHrP inhibits transforming growth factor-␤ -stimulated release of dipeptidyl peptidase II, a glial enzyme involved in glial scarring (Struckhoff 1995).…”

mentioning

confidence: 99%

Immunohistochemical Detection of Parathyroid Hormone-related Protein in Human Astrocytomas

Miguel¹,

Sarasa²,

López–Ferro³

et al. 1998

J Histochem Cytochem.

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P arathyroid hormone-related protein (PTHrP) was initially isolated from tumors associated with humoral hypercalcemia of malignancy and has since been identified in many normal tissues, in which it appears to act as an auto/paracrine growth/differentiation factor (Philbrick et al. 1996).Neurons from different subregions of the rat brain, including the cerebellum and the hippocampus, express PTHrP and PTH/PTHrP receptors (Weir et al. 1990;Ureña et al. 1993). In the rat, PTHrP has also been detected in the meninges but not in astrocytes that have PTH/PTHrP receptors (Struckhoff and Turzynski 1995). We evaluated the presence of PTHrP in human astrocytomas, using immunohistochemistry and Western immunoblot analysis.Four low-grade astrocytomas and five high-grade astrocytomas (Daumas-Duport et al. 1988) were studied. Fresh tumor samples were fixed overnight in 10% buffered formalin and embedded in paraffin before sectioning. The histological features were evaluated on hematoxylin-and eosin-stained tumor sections. Cytologically, the constituent tumor cells varied in size and in histological appearance. They consisted of small cells with hyperchromatic nuclei and larger cells with glassy cytoplasm and the morphological appearance of astrocytes.Immunostainings were performed with anti-PTHrP antisera C6 and C13, recognizing the C-and N-terminal region of PTHrP, respectively (Albar et al. 1996), and MIB 1 monoclonal specific antibody (Immunotech; Marseille, France), recognizing the Ki-67 proliferation marker, at 1:100 dilution, by the avidin-biotinperoxidase complex method. Paraffin-embedded tissue sections (5 m) were mounted on glass slides pretreated with 1 g/liter poly-l -lysine hydrobromide (Sigma; St Louis, MO). After heating at 60 Њ C for 12-24 hr, tissue samples were deparaffinized with xylene and rehydrated through a series of graded ethanols. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide for 5 min. Then the tissue sections for PTHrP staining were treated with 0.1% trypsin for 5 min and then blocked with 10% nonspecific porcine serum for 10 min. Tissue samples for MIB 1 staining, in 10 mM sodium citrate buffer, pH 6, were boiled for 2 min under pressure. Incubations were carried out in a humidified chamber for 2 hr at room temperature (RT). Positive staining was developed with 3,3 Ј -diaminobenzidine (Sigma) for 10 min. As negative controls, some tumor sections were incubated with saline buffer instead of the primary antiserum.Positive immunostaining for PTHrP was found in all nine astrocytomas with antisera C6 and C13. With either antiserum, the staining was diffuse in the cytoplasm of neoplastic cells and was prominent in the larger cells with a more astrocytic appearance ( Figures 1A and 1B). These cells were abundant in the five high-grade astrocytomas, whose proliferative activity, expressed as percentage of MIB 1-positive nuclear area was (mean Ϯ SD) 17 Ϯ 5%, greater than 5 Ϯ 3% in the four low-grade cases. Adjacent non-neoplastic cortex in the tissue samples did not stain for PTHrP. ...

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Astrocytic and neuronal localization of the scaffold protein Na⁺/H⁺ exchanger regulatory factor 2 (NHERF‐2) in mouse brain

Paquet

Kuwajima

Yun

et al. 2005

J of Comparative Neurology

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The Na + /H + exchanger regulatory factor 2 (NHERF-2) is a scaffold protein that regulates cellular signaling by forming protein complexes. Several proteins known to interact with NHERF-2 are abundantly expressed in the central nervous system, but little is known about NHERF-2 localization in the brain. By using immunohistochemistry combined with light and electron microscopy, we found that many populations of astrocytes, as well as some populations of neurons, were immunopositive for NHERF-2 throughout the mouse brain. Quantitative analysis of the subcellular distribution of NHERF-2 immunostaining in four brain structures, cerebral cortex, hippocampus, striatum, and cerebellar cortex, showed that NHERF-2 was expressed mainly in astrocytic processes but was also sometimes observed in both pre-and postsynaptic neuronal elements. NHERF-2 immunostaining was associated mainly with the plasma membrane of neurons and astrocytes. However, NHERF-2 immunoreactivity was also observed in association with synaptic vesicles in putative glutamatergic axon terminals. The subcellular localization of NHERF-2 in brain is consistent with a role for NHERF-2 in forming complexes between cell surface and cytosolic proteins, and the preferential expression of NHERF-2 in astrocytes suggests that this scaffold protein may play an important role in astrocytic physiology. Indexing termsPDZ; E3KARP; NHERF2; scaffolding; receptor; signaling Scaffold proteins play an important role in regulating cellular signaling by physically tethering together key molecular components of signaling pathways. Many scaffold proteins consist of a series of modular domains that bind to specific motifs on target proteins. For example, NHERF-2 (also known as E3KARP, SIP-1, and TKA-1) is a scaffold protein that contains two PDZ domains and one ERM-binding domain (Yun et al., 1997). PDZ domains are named for the first three proteins in which they were described (postsynaptic density-95, discs large, zona occludens-1) and mediate protein-protein interactions by binding to the last few carboxyl- terminal residues of their target proteins (Hung and Sheng, 2002). ERM (ezrin, ra-dixin, moesin)-binding domains link NHERF-2 and the related scaffold NHERF-1 to the actin cytoskeleton by interacting with the ERM family of actin-binding proteins (Nguyen et al, 2001). Thus, via these multiple domains, NHERF-2 can link its interacting partners to each other and to the actin cytoskeleton.The PDZ domains of NHERF-2 are known to interact with a handful of specific G proteincoupled receptors (GPCRs), growth factor receptors, ion channels, transporters, and cellular signaling effectors (Shenolikar et al., 2004). By recruiting protein targets and forming protein complexes, NHERF-2 can regulate the targeting and/or trafficking of its binding partners as well as their physiological functions. For example, the simultaneous interaction of NHERF-2 with phospholipase Cβ (PLCβ) and either the purinergic P2Y 1 receptor or lysophosphatidic acid LPA 2 receptor results in enhanced rece...

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Demonstration of parathyroid hormone-related protein in meninges and its receptor in astrocytes: evidence for a paracrine meningo-astrocytic loop

Cited by 27 publications

References 44 publications

Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Immunohistochemical Detection of Parathyroid Hormone-related Protein in Human Astrocytomas

Astrocytic and neuronal localization of the scaffold protein Na⁺/H⁺ exchanger regulatory factor 2 (NHERF‐2) in mouse brain

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Demonstration of parathyroid hormone-related protein in meninges and its receptor in astrocytes: evidence for a paracrine meningo-astrocytic loop

Cited by 27 publications

References 44 publications

Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Immunohistochemical Detection of Parathyroid Hormone-related Protein in Human Astrocytomas

Astrocytic and neuronal localization of the scaffold protein Na+/H+ exchanger regulatory factor 2 (NHERF‐2) in mouse brain

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Astrocytic and neuronal localization of the scaffold protein Na⁺/H⁺ exchanger regulatory factor 2 (NHERF‐2) in mouse brain