Differential Efficacies of Somatostatin Receptor Agonists for G-Protein Activation and Desensitization of Somatostatin Receptor Subtype 4-Mediated Responses

Engström, Mia; Savola, Juha‐Matti; Wurster, Siegfried

doi:10.1124/jpet.105.094128

Cited by 29 publications

(20 citation statements)

References 32 publications

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“…Thus, agonist stimulation of GTPγS binding reflects receptor activation of all receptor-interacting G proteins, including the pertussis toxin sensitive G proteins that couple somatostatin receptors to adenylyl cyclase and the pertussis toxin insensitive G proteins that are at least partially responsible for coupling receptors to phospholipase C. Further, since cyclic AMP measurements were made after 15 min of agonist stimulation whereas phosphoinositide production was determined after 50 min of stimulation, the effect of receptor desensitization will differ in the two assays. We now know that desensitization can occur after few minutes of agonist stimulation for several somatostatin receptor subtypes (Beaumont et al, 1998;Elberg et al, 2002;Engstrom et al, 2006;Hipkin et al, 1997;Holliday et al, 2007;Liu et al, 2000). Thus, desensitization will influence second messenger formation in assays conducted in intact cells and the impact of desensitization on such measurements will vary with the time of incubation.…”

Section: Functionally Selective Agonists At Somatostatin Receptorsmentioning

confidence: 99%

“…Using cytosensor microphysiometry, two groups have reported differential agonist activity at sst4 receptors (Engstrom et al, 2006;Smalley et al, 1998). Both groups measured analog stimulation of the extracellular acidification rate (EAR), which results from activation of the Na+/H+ antiporter via pertussis toxin sensitive G proteins.…”

Section: Functionally Selective Agonists At Somatostatin Receptorsmentioning

confidence: 99%

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Selective agonism in somatostatin receptor signaling and regulation

Schönbrunn¹

2008

Molecular and Cellular Endocrinology

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SummaryThe five somatostatin receptor subtypes, named sst1 to sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation. Until recently it was believed that once a particular somatostatin receptor was activated by an agonist, all the downstream signaling and regulatory effects characteristic of that receptor subtype in that cellular environment would be triggered. Thus, differences in the actions of somatostatin analogs between tissues were attributed to variability in the nature and concentration of the sst receptor subtypes and effectors expressed in different targets. However, agonists have recently been shown to exhibit functional selectivity at individual sst receptors such that they can elicit a subset of that receptor's potential effects, a property known as biased agonism. This review will summarize the evidence for functionally selective somatostatin receptor agonists and discuss the implications and promise of these new findings.

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Section: Functionally Selective Agonists At Somatostatin Receptorsmentioning

confidence: 99%

Section: Functionally Selective Agonists At Somatostatin Receptorsmentioning

confidence: 99%

Selective agonism in somatostatin receptor signaling and regulation

Schönbrunn¹

2008

Molecular and Cellular Endocrinology

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“…4), and a reduced but significant (12 Ϯ 2%) inhibition in SST 2 knock-out mice ( p Ͻ 0.05; n ϭ 5). J-2156 is a newly available high affinity nonpeptide SST 4 agonist (Engstrom et al, 2006). Superfusion of 1 M J-2156 resulted in a 21.8 Ϯ 3% inhibition of bursting in wild-type mice ( p Ͻ 0.05) ( Table 4) and had no effect on SST 4 knock-out mice ( p Ͼ 0.05; n ϭ 5).…”

Section: Pharmacological Validation Of Receptor Knock-out Studiesmentioning

confidence: 99%

Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

Qiu

Zeyda²,

Johnson³

et al. 2008

J. Neurosci.

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The K ϩ M-current (I M , Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augments I M in hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples to I M and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST 2 , SST 3 , and SST 4 receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in the SST 4 knock-outs. When seizures were induced by systemic injection of kainate, only SST 4 knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST 2 and SST 4 appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I M in CA1 pyramidal neurons of wild-type and SST 2 knock-out mice, but not SST 4 knock-out mice. Using M-channel blockers, we found that SST 4 coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I M that is important in controlling seizure activity. SST 4 receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.

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“…J-2156, a peptidomimetic analogue of somatostatin is a superagonist of the somatostatin receptor 4 subtype but does not cause desensitization. 35 This makes it clinically useful for controlling cellular proliferation in tumorous tissues. The OT antagonist atosiban, which is used clinically for preventing preterm birth, inhibits Gq and concomitantly stimulates Gi, leading to MAPK activation and cell proliferation.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Jean-Alphonse¹,

Perkovska²,

Frantz

et al. 2009

Journal of the American Society of Nephrology

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X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV 2 R). Most of these mutations lead to intracellular retention of the hV 2 R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV 2 Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV 2 R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV 2 R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV 2 R agonist pharmacochaperones promising therapeutic candidates for cNDI. The antidiuretic hormone arginine-vasopressin (AVP) is crucial for osmoregulation, cardiovascular control, and water homeostasis. The human AVP V 2 receptor (hV 2 R), localized in the principal cells of the kidney collecting duct, mediates AVP antidiuretic effect and therefore helps in maintaining physiologic plasma osmolality, blood volume, and arterial pressure. Binding of AVP to hV 2 R first triggers a cAMP signal through activation of the G protein ␣ s (Gs) subunit and adenylyl cyclase (AC). Then, the cAMP-activated protein kinase A phosphorylates aquaporin 2 water channels, resulting in their insertion into the luminal membrane of principal cells and finally to water reabsorption. 1 AVP binding to hV 2 R also induces arrestin recruitment, receptor internalization, 2 and mitogen-activated protein kinase (MAPK) activation. 3 Mutations in the hV 2 R gene lead to the X-linked congenital nephrogenic diabetes insipidus (cNDI), a rare disease characterized by the kidney's inability to concentrate urine despite normal or elevated plasma concentrations of AVP. 4 More than 200 different mutations have been described and are responsible for polyuria, a main consequence of the disease. Most of the mutant receptors (cNDIhV 2 Rs), trapped in the endoplasmic reticulum

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Differential Efficacies of Somatostatin Receptor Agonists for G-Protein Activation and Desensitization of Somatostatin Receptor Subtype 4-Mediated Responses

Cited by 29 publications

References 32 publications

Selective agonism in somatostatin receptor signaling and regulation

Selective agonism in somatostatin receptor signaling and regulation

Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

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