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CXCL12 modulates vasopressin in the rat
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Abstracts / Frontiers in Neuroendocrinology 27 (2006) 120–128
Conversely, blockade of PACAP receptors can reduce local VP release from the SON of osmotically stimulated rats, suggesting that these receptors contribute to local VP release during physiological demand. To begin to elucidate PACAP-mediated signaling during osmotic stimulation, we tested whether local VP release from SON tissue punches prepared from osmotically stimulated rats is dependent on cAMP/PKA signaling, to which PACAP receptors couple directly. Incubation with PKA inhibitor Rp-cAMPS (100 lM) reduced osmotically stimulated release of both VP and NO, suggesting that NO production is dependent on PKA activity. Cyclic AMP/PKA signaling can also lead indirectly to stimulation of nitric oxide synthase (NOS) activity (Xu and Krukoff, 2005). Consistent with this idea, we also found that NO production is critical for both osmotically stimulated and PACAP-elicited local VP release, which is sensitive to blockade by the NOS inhibitor L-NMMA. These findings suggest that NO signaling occurs downstream of PACAP receptor stimulation in the SON. We then examined whether direct stimulation of endogenous cAMP production alone could mimic the effects of PACAP on local VP release from normosmotic rat SON. The adenylate cyclase activator MPB forskolin significantly stimulated NO as well as VP release from SON punches, relative to untreated punches. This enhancement of local NO and VP release in response to MPB forskolin was eliminated by pretreatment with L-NMMA (700 nM), suggesting that NO production downstream of cAMP/PKA signaling is critical for cAMP-induced local VP release. To test the involvement of cAMP/PKA-stimulated NO production in PACAP receptor-dependent enhancement of local VP release during osmotic stimulation, we measured the release of NO (and VP) from SON punches prepared from normosmotic rats, and osmotically stimulated rats in the presence and absence of the PACAP receptor antagonist PACAP6-27 (100 nM). Enhancement of local NO (and VP) release in stimulated rat SON punches was eliminated by incubation with PACAP6-27. Collectively, these results suggest that PACAP released in the SON during osmotic activation stimulates local VP release by enhancing NOS activity in the SON consequent to activation of cAMP/PKA signaling.
The chemokine SDF-1/CXCL12 modulates vasopressin in the rat Ce´line Callewaere a, Arlette Burlet b, Ghazal Banisadr a,c, Michel G. Desarmenien d, Patricia Mechighel a, b b Brigitte Fernette , Ste´phanie Blanchard , Patrick Kitabgi a, Ste´phane Melik Parsadaniantz a, William Rostene a a INSERM-UPMC U732, Hoˆpital Saint-Antoine, Paris, France b EA 3453, Lab Biologie Cellulaire, Nancy, France c Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, USA d IGF CNRS UMR 5203 INSERM U661, University Montpellier I et II, Montpellier, France
doi:10.1016/j.yfrne.2006.03.331
doi:10.1016/j.yfrne.2006.03.338
Chemokines are small secreted proteins originally defined as chemoattractants for leucocytes and to play a key role in inflammation. We and others recently demonstrated that they are constitutively expressed by different cell types including neurons in the normal brain, suggesting that they may act as modulators of neuronal functions. We further provided immunohistochemical evidence that the chemokine SDF-1 and its unique receptor CXCR4 are constitutively and regionally expressed in the hypothalamus where they are exclusively co-localized with vasopressin (AVP) neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). We observed that SDF-1 can blunt the autoregulation of AVP release in vitro and counteract angiotensin II-induced plasma AVP release in vivo. The Brattleboro rat is known to present diabetes insipidus due to impaired synthesis of bioactive AVP. SDF-1 and CXCR4 immunoreactivity are dramatically decreased in the Brattleboro rats as compared to controls in strict correlation with the decrease in AVP expression in PVN and SON of Brattleboro rats. When homozygous Brattleboro rats were treated with an AVP analog in order to restore peripheral AVPergic renal function, SDF-1 and CXCR4 immunoreactivity remained at the low level observed in control animals, suggesting a central deficit in SDF-1/ CXCR4 expression. These original findings suggest that the chemokinergic system SDF-1/CXCR4 could be involved in the modulation of AVP-mediated neuroendocrine functions.
Abstracts / Frontiers in Neuroendocrinology 27 (2006) 120–128
Conversely, blockade of PACAP receptors can reduce local VP release from the SON of osmotically stimulated rats, suggesting that these receptors contribute to local VP release during physiological demand. To begin to elucidate PACAP-mediated signaling during osmotic stimulation, we tested whether local VP release from SON tissue punches prepared from osmotically stimulated rats is dependent on cAMP/PKA signaling, to which PACAP receptors couple directly. Incubation with PKA inhibitor Rp-cAMPS (100 lM) reduced osmotically stimulated release of both VP and NO, suggesting that NO production is dependent on PKA activity. Cyclic AMP/PKA signaling can also lead indirectly to stimulation of nitric oxide synthase (NOS) activity (Xu and Krukoff, 2005). Consistent with this idea, we also found that NO production is critical for both osmotically stimulated and PACAP-elicited local VP release, which is sensitive to blockade by the NOS inhibitor L-NMMA. These findings suggest that NO signaling occurs downstream of PACAP receptor stimulation in the SON. We then examined whether direct stimulation of endogenous cAMP production alone could mimic the effects of PACAP on local VP release from normosmotic rat SON. The adenylate cyclase activator MPB forskolin significantly stimulated NO as well as VP release from SON punches, relative to untreated punches. This enhancement of local NO and VP release in response to MPB forskolin was eliminated by pretreatment with L-NMMA (700 nM), suggesting that NO production downstream of cAMP/PKA signaling is critical for cAMP-induced local VP release. To test the involvement of cAMP/PKA-stimulated NO production in PACAP receptor-dependent enhancement of local VP release during osmotic stimulation, we measured the release of NO (and VP) from SON punches prepared from normosmotic rats, and osmotically stimulated rats in the presence and absence of the PACAP receptor antagonist PACAP6-27 (100 nM). Enhancement of local NO (and VP) release in stimulated rat SON punches was eliminated by incubation with PACAP6-27. Collectively, these results suggest that PACAP released in the SON during osmotic activation stimulates local VP release by enhancing NOS activity in the SON consequent to activation of cAMP/PKA signaling.
The chemokine SDF-1/CXCL12 modulates vasopressin in the rat Ce´line Callewaere a, Arlette Burlet b, Ghazal Banisadr a,c, Michel G. Desarmenien d, Patricia Mechighel a, b b Brigitte Fernette , Ste´phanie Blanchard , Patrick Kitabgi a, Ste´phane Melik Parsadaniantz a, William Rostene a a INSERM-UPMC U732, Hoˆpital Saint-Antoine, Paris, France b EA 3453, Lab Biologie Cellulaire, Nancy, France c Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, USA d IGF CNRS UMR 5203 INSERM U661, University Montpellier I et II, Montpellier, France
doi:10.1016/j.yfrne.2006.03.331
doi:10.1016/j.yfrne.2006.03.338
Chemokines are small secreted proteins originally defined as chemoattractants for leucocytes and to play a key role in inflammation. We and others recently demonstrated that they are constitutively expressed by different cell types including neurons in the normal brain, suggesting that they may act as modulators of neuronal functions. We further provided immunohistochemical evidence that the chemokine SDF-1 and its unique receptor CXCR4 are constitutively and regionally expressed in the hypothalamus where they are exclusively co-localized with vasopressin (AVP) neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). We observed that SDF-1 can blunt the autoregulation of AVP release in vitro and counteract angiotensin II-induced plasma AVP release in vivo. The Brattleboro rat is known to present diabetes insipidus due to impaired synthesis of bioactive AVP. SDF-1 and CXCR4 immunoreactivity are dramatically decreased in the Brattleboro rats as compared to controls in strict correlation with the decrease in AVP expression in PVN and SON of Brattleboro rats. When homozygous Brattleboro rats were treated with an AVP analog in order to restore peripheral AVPergic renal function, SDF-1 and CXCR4 immunoreactivity remained at the low level observed in control animals, suggesting a central deficit in SDF-1/ CXCR4 expression. These original findings suggest that the chemokinergic system SDF-1/CXCR4 could be involved in the modulation of AVP-mediated neuroendocrine functions.