Pharmacological characterization of CCKB receptors in human brain: no evidence for receptor heterogeneity

Kinze, Stephan; Schöneberg, Torsten; Meyer, R.; Martin, H; Kaufmann, Roland

doi:10.1016/0304-3940(96)13026-3

Cited by 7 publications

(3 citation statements)

References 19 publications

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“…The CCK B R is a particularly important drug target because of its widespread expression throughout the central nervous system and in certain peripheral tissues, including stomach, pancreas, and smooth muscle. In the central nervous system, the major form of CCK is the C-terminally sulfated cholecystokinin octapeptide (CCK-8s) and the CCK B R is the predominant subtype with the highest receptor densities found in the cortex regions and nucleus caudatus (2). Binding of CCK to the CCK B R in the central nervous system increases the rate of release of dopamine and causes interference with the action of opioids where CCK is suggested to be a specific opiate antagonist in the analgesiamediating system implicated in the perception of pain (3)(4)(5).…”

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confidence: 99%

Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor

Anders

Blüggel

et al. 1999

Biochemistry

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In investigating the agonist binding site of the human brain cholecystokininB receptor (CCKBR), we employed the direct protein chemical approach using a photoreactive tritiated analogue of sulfated cholecystokinin octapeptide, which contains the p-benzoylbenzoyl moiety at the N-terminus, followed by purification of the affinity-labeled receptor to homogeneity. This probe bound specifically, saturably, and with high affinity (KD = 1.2 nM) to the CCKBR and has full agonistic activity. As the starting material for receptor purification, we used stably transfected HEK 293 cells overexpressing functional CCKBR. Covalent labeling of the WGA-lectin-enriched receptor revealed a 70-80 kDa glycoprotein with a protein core of about 50 kDa. Identification of the agonist binding site was achieved by the application of subsequent chemical and enzymatical cleavage to the purified receptor. A radiolabeled peptide was identified by Edman degradation amino acid sequence analysis combined with MALDI-TOF mass spectrometry. The position of the radioactive probe within the identified peptide was determined using combined tandem electrospray mass spectrometry and peptide mapping. The probe was covalently attached within the sequence L52ELAIRITLY61 that represents the transition between the N-terminal domain and predicted transmembrane domain 1. Using this interaction as a constraint to orientate the ligand within the putative receptor binding site, a model of the CCK-8s-occupied CCKBR was constructed. The hormone was found to be placed in a binding pocket built from both extracellular and transmembrane domains of CCKBR with its N-terminus mainly interacting with residues Arg57 and Tyr61.

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confidence: 99%

Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor

Anders

Blüggel

et al. 1999

Biochemistry

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“…Obrada impulsa u mozdanoj kori veoma je slozena, posebno u oblastima sa slozenim funkcijama kakav je LPI. Verovatno nije slucajno da je CCK najzastupljeniji peptid u mozdanoj kori [12] ukljucujuci LPI [1], ada je najveca gustina CCK IR neurona medu kortikalnim oblastima u temenom reznju [6].…”

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Morphological and laminar distribution of cholescystokinine - immunoreactive neurons in cortex of human inferior parietal lobule and their clinical significance

Puškaš¹,

Draganić-Gajić

Malobabić³

et al. 2008

Med pregl

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“…82,83 Both CCK and opioids are localized within principal nociceptive centres, including layers I and II of the spinal cord, the periaqueductal grey (PAG), and intralaminar nuclei of the thalamus. [84][85][86][87][88][89][90] They also coexist in some neurones of the thalamus, PAG and allocortex. 91,92 Thus, anatomical considerations allow an opportunity for cross-talk between opioidergic and CCK-ergic signalling.…”

Section: Cross-talk Between Cck and Opioid Signallingmentioning

confidence: 99%

Signal transduction in neuropathic pain, with special emphasis on the analgesic role of opioids - Part II: Moving basic science towards a new pharmacotherapy

McCormack¹

1999

Pain Reviews

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In the first part of this three-part article I explored the notion that pharmacological intervention, aimed at eliminating abnormal sensations such as hyperalgesia or paraesthesia arising as a direct result of nerve injury, activates adaptive responses that ensure adequacy of neurotransmission, regardless of whether such transmission ultimately evokes normal or abnormal sensations. Thus, by their nature, such adaptive responses will act to oppose and surmount any drug-induced intervention designed to diminish pain through attenuation of signal conduction. A corollary of this hypothesis is that even the most sophisticated novel pharmacological entities, when used to block the pain signal, represent substrates for evoking a repertoire of failsafe mechanisms that have evolved throughout a history of challenge and response. In Part II, I explore in greater depth how activation of these responses may explain why the treatment of neuropathic pains, particularly with opioids, can be so frustrating. Opioid analgesia and cholecystokinin CCK as an anti-analgesic peptide Numerous reports have indicated that CCK antagonizes opioid antinociceptive effects. Indeed, administered by peripheral or central (intracerebroventricular (i.c.v.), intrathecal (i.t.)) routes, CCK can reduce morphine-, PL017-or ohmefentanyl-(two selective µ-agonists), and β-endorphininduced analgesia, as well as the morphineinduced depression of the nociceptive flexion reflex in rats. 19-27 In the mouse tail-flick test, CCK attenuates the analgesic effects of morphine. 28 In addition, in the same species, CCK administered i.t. antagonizes the inhibition of tail flick by i.c.v. β-endorphin. 29 Furthermore, the inhibitory effect of morphine and [D-Ala 2-Me)Phe 4-Glyol 5 ] enkephalin (DAMGO) on C-fibre-evoked activity of rat spinal nociceptive neurones can be reduced by CCK. 30-33 Thus, from these data, it can be concluded that CCK has the pharmacological property of reducing the antinociceptive effects of endogenous opioids.

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Pharmacological characterization of CCKB receptors in human brain: no evidence for receptor heterogeneity

Cited by 7 publications

References 19 publications

Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor

Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor

Morphological and laminar distribution of cholescystokinine - immunoreactive neurons in cortex of human inferior parietal lobule and their clinical significance

Signal transduction in neuropathic pain, with special emphasis on the analgesic role of opioids - Part II: Moving basic science towards a new pharmacotherapy

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Pharmacological characterization of CCKB receptors in human brain: no evidence for receptor heterogeneity

Cited by 7 publications

References 19 publications

Direct Identification of the Agonist Binding Site in the Human Brain CholecystokininB Receptor

Direct Identification of the Agonist Binding Site in the Human Brain CholecystokininB Receptor

Morphological and laminar distribution of cholescystokinine - immunoreactive neurons in cortex of human inferior parietal lobule and their clinical significance

Signal transduction in neuropathic pain, with special emphasis on the analgesic role of opioids - Part II: Moving basic science towards a new pharmacotherapy

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Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor

Direct Identification of the Agonist Binding Site in the Human Brain Cholecystokinin_B Receptor