Pharmacological analysis of [<sup>3</sup>H]‐senktide binding to NK<sub>3</sub> tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes

Guard, Steven; Watson, Steve P.; Maggio, John E.; Too, Heng‐Phon; Watling, Keith J.

doi:10.1111/j.1476-5381.1990.tb13004.x

Cited by 90 publications

(28 citation statements)

References 35 publications

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“…The most interesting observation from these studies is that while eledoisin is approximately 15-fold less potent than either senktide or NKB at the human NK-3 receptor (Fig. 3B and C), all three neuropeptides display a similarly high affinity for the NK-3 receptor in some animal tissue preparations such as guinea pig ileum [5]. This potentially distinct pharmacological property of human NK-3 may account in part for the reported inability to detect this receptor in human brain using [~:~I]eledoisin [6].…”

Section: G2mentioning

confidence: 89%

“…Pharmacological and biochemical studies, as well as molecular cloning, have shown that all three neurokinin receptors are members of the G-proteincoupled receptor super-family possessing seven putative transmembrane regions [4]. NK-3 receptors have been identified in membranes from guinea pig myenteric plexus and cerebral cortex [5] as well as brain slices of rat, mouse and guinea pig [2,3,6,7]. NK-3 receptors also mediate increased phosphoinositide hydrolysis in guinea pig ileum and neonatal rat spinal cord [2,8].…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Buell¹,

Schulz²,

Arkinstall³

et al. 1992

FEBS Letters

101

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The complete amino acid sequence of the human neurokinin-3 receptor was deduced by DNA sgqumtco analysis of human genomic fragments. Comparison of the predicted primary structure with those for the human neurokinin receptors 1 and 2 shows a highly conserved pattern of seven hydrophobi¢ regions with maximum divergence oceuring at the amino-and carboxy-terrnini, The position of intron-exon junctions are identical to those in other reported neurokinin genes, Using a chimeric genomic.cDNA gone, the human NK-3 receptor was expressed in Xenopus laevts oooytes where it mediates membrane conductance changes in response to its agonist, neurokinin B. More significantly, expression of the 8ene in mammalian cells resulted in detection of receptor binding as well as neurokinin-stimulated calcium mobilization and araehidonie acid release, all displaying the pharmacological characteristics expected of a nearokinin-3 receptor, By using the polymerase chain reaction we have shown that mRNA for the human neurokinin-3 receptor is expressed predominantly in the egntral nervous system,

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Section: G2mentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Buell¹,

Schulz²,

Arkinstall³

et al. 1992

FEBS Letters

101

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“…The NK-3 receptor is believed to be the neuronal tachykinin receptor (Guard, Watson, Maggio, Phon Too & Watling, 1990). Both SP and senktide mimic the sEPSP because NK-3-mediated responses are associated with a membrane depolarization, an increase in resistance, an inhibition of resting gK and inhibition of spike-activated 9Kca Hanani et al 1988;Morita & Katayama, 1992).…”

mentioning

confidence: 99%

Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea‐pig myenteric neurones.

Bertrand

Galligan

1994

The Journal of Physiology

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1. Single electrode voltage clamp recordings were obtained from myenteric neurones of guinea-pig ileum in vitro. Slow excitatory postsynaptic currents (sEPSCs) were elicited by focal stimulation of interganglionic nerve strands in twenty-four of thirty neurones more than 30 min after impalement. In seventeen of twenty-four neurones, sEPSCs were associated with a conductance decrease and reversed polarity at -96 + 3 mV (near the reversal potential for potassium, EK); this response was due to inhibition of resting potassium conductance, gK. In seven of twenty-four neurones, there was either no net conductance change or a biphasic conductance change during the sEPSC; a reversal potential for peak currents could not be determined. 2. Application of senktide (3/uM), a neurokinin-3 receptor agonist, caused an inward current in forty-one of fifty-three neurones more than 30 min after impalement. In twenty of forty-one neurones, senktide-induced currents were due to inhibition of resting gK. In eleven of forty-one neurones there was either no net conductance change or a biphasic conductance change; a reversal potential for peak currents could not be determined. In ten out of forty-one neurones, senktide-induced currents were associated with a conductance increase (ginc); the estimated reversal potential was -17 + 3 mV.3. Application of forskolin (1 ,lM) caused an inward current that occluded the decrease in gK caused by senktide and the sEPSC. In neurones in which sESPCs and senktide responses were associated with an unclear or biphasic conductance change, forskolin did not reduce the peak current and residual currents were usually associated with a gin, 4. In neurones in which senktide-induced currents were associated with a gin, reducing extracellular Cl-to 13 mm reduced senktide-induced currents by 79%. Reducing extracellular Na+, or adding tetraethylammonium (TEA, 50 mM), cobalt (2 mM) or picrotoxin (30 ,lM) did not change senktide-induced currents. The chloride transport/ channel blockers niflumic acid and mefenamic acid (both at 100 /SM) blocked senktideinduced currents. It was concluded that senktide increases chloride conductance (gcl).5. Chord conductance measurements made between -70 and -90 mV during sEPSCs were used to determine the contribution of an increase in gcl to sEPSCs. These measurements indicated that the peak sEPSC is composed of a 90% decrease in g9 and a 10% increase in gcl. Similar data were obtained from measurements made during senktide responses.It was concluded that senktide-induced currents and sEPSCs are due to a concurrent decrease in g9 and an increase in gcl in a subset of myenteric neurones.

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“…Senktide binds selectively to both central and peripheral NK3 receptors with high affinity (Guard et al, 1990). The high potency and relatively weak efficacy of senktide in rat ganglia thus provides evidence for the presence of an NK3 receptor subtype.…”

Section: Discussionmentioning

confidence: 97%

“…The NK3-selective ligand, senktide (Wormser et al, 1986;Guard et al, 1990) proved to be the most potent ligand examined with an EC50 of 4 nM, although the maximum depolarization produced in rat ganglia was only 27% that of eledoisin and smaller than that of alternative agonists (Figure la and b). Similarly the NKI-selective ligands, SP, Sar-Met-SP and SPOMe, all exhibited maximal depolariza- The resultant depolarizations in the same ganglia were normalized to the control response with eledoisin.…”

Section: Resultsmentioning

confidence: 99%

Differences in neurokinin receptor pharmacology between rat and guinea‐pig superior cervical ganglia

Seabrook

Main

Bowery

et al. 1992

British J Pharmacology

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1 The depolarizations elicited by seven neurokinin receptor agonists were examined in both rat and guinea-pig superior cervical ganglia by use of grease-gap methodology in the presence of tetrodotoxin (0.1 pM). Responses were normalised with respect to 1 AM eledoisin.2 The rank order of agonist potency in the rat ganglia was senktide > substance P > substance P methyl ester = eledoisin = Sar-Met-substance P > neurokinin B > neurokinin A, whereas in guinea-pig superior cervical ganglion (SCG) the rank order was senktide > Sar-Met-substance P > neurokinin B = eledoisin = substance P methyl ester. The concentration-effect curves for substance P and neurokinin A in guinea-pig ganglia were biphasic which precluded the determination of meaningful potency values. 3 The maximal depolarization achieved by subtype selective ligands was different between these two species. On rat and guinea-pig SCG, the NK3-selective ligand, senktide, produced a maximal depolarization of 27% and 274% respectively, whereas the NK,-selective ligand, substance P methyl ester, produced depolarizations of 77% and 64% respectively. 4 The depolarizations induced by substance P methyl ester and senktide in either species were unaffected by atropine (1 pM), suggesting a lack of involvement of presynaptic neurokinin receptors in the generation of the response. 5 The potency of substance P methyl ester, senktide, and neurokinin A were unaffected by pretreating ganglia with the peptidase inhibitors bacitracin (40pgmlm'), leupeptin (4fpgmhl'), and chymostatin (2 g ml-1). Similarly, these peptidase inhibitors had no effect on the maximal depolarizations achieved by any of these agonists. 6 It is evident that rat and guinea-pig superior cervical ganglia possess both NK, and NK3 receptors, but that their net contribution to depolarizations are different between the two species. The depolarizations in guinea-pig SCG are mediated predominantly by an NK3 subtype and in rat SCG by an NK, receptor subtype.

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Pharmacological analysis of [³H]‐senktide binding to NK₃ tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes

Cited by 90 publications

References 35 publications

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea‐pig myenteric neurones.

Differences in neurokinin receptor pharmacology between rat and guinea‐pig superior cervical ganglia

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Pharmacological analysis of [3H]‐senktide binding to NK3 tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes

Cited by 90 publications

References 35 publications

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea‐pig myenteric neurones.

Differences in neurokinin receptor pharmacology between rat and guinea‐pig superior cervical ganglia

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Pharmacological analysis of [³H]‐senktide binding to NK₃ tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes