Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

Drake, William; Lowe, Sarah R.; Mirtella, Adriana; Bartlett, T. J.; Clark, Adrian

doi:10.1677/joe.0.1650133

Cited by 21 publications

(9 citation statements)

References 22 publications

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“…Interestingly, CGRP relaxes vascular smooth muscle via a G–protein‐coupled mechanism, resulting in a rise in intracellular cAMP. This inhibition also shows a desensitization on repeated application of CGRP, similar to that seen here [32]. It is known that a rise in cAMP produces a similar reduction in frequency and amplitude of the phasic activity [33].…”

Section: Discussionsupporting

confidence: 82%

Inhibitory actions of calcitonin gene‐related peptide and capsaicin: evidence for local axonal reflexes in the bladder wall

Gillespie

2004

BJU International

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changes in the frequency and amplitude of phasic activity generated by muscarinic stimulation; an initial burst of activity involving a rise in frequency, a second phase of reduced amplitude and frequency and a third phase where the amplitude of the transients recovered and the frequency increased. Capsaicin had no effect on the phasic activity generated by the nicotinic ligand lobeline (30 m mol/L). As capsaicin releases the neurotransmitter content of the sensory nerves, experiments explored the actions of CGRP and substance P on the muscarinic-induced activity. CGRP (3-30 nmol/L) reduced the amplitude and slowed the frequency of the phasic activity. On washing off CGRP the amplitude and frequency of the transient activity recovered and there was a transient increase in frequency above the levels before stimulation. There was also evidence of a desensitization to CGRP on repeated application. In contrast, substance P (100-300 nmol/L) increased the frequency of the transients, while on removing it there was an inhibition of both amplitude and frequency. CONCLUSIONSThese results suggest that neurotransmitters released from sensory nerve endings in the guinea pig bladder wall affect phasic activity. The direct application of CGRP inhibited phasic activity while substance P was excitatory, indicating the specific contributions of these neurotransmitters. The excitation after stimulation with CGRP and inhibition with substance P may indicate that these neurotransmitters feed back on the sensory nerves to induce transmitter release. Taken together, these observations suggest the presence of a local reflex in the bladder wall, where axon collaterals of afferent sensory fibres innervate the pacemaker mechanism in the bladder wall responsible for generating phasic activity. The possible importance of this reflex in the physiology and pathophysiology of the bladder is discussed.

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Section: Discussionsupporting

confidence: 82%

Inhibitory actions of calcitonin gene‐related peptide and capsaicin: evidence for local axonal reflexes in the bladder wall

Gillespie

2004

BJU International

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“…1988; Kawasaki, 2002). Independent of the endothelium, the release of CGRP from sensory nerve terminals can evoke vasodilatation through activation of CGRP receptors on vascular smooth muscle cells, thereby stimulating protein kinase A to reduce [Ca 2+ ] i and promote relaxation (Drake et al . 2000; Brain & Grant, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…2A-C) is consistent with inhibiting the vasodilator actions of perivascular sensory nerves (Bevan & Brayden, 1987;Kawasaki et al 1988;Kawasaki, 2002). Independent of the endothelium, the release of CGRP from sensory nerve terminals can evoke vasodilatation through activation of CGRP receptors on vascular smooth muscle cells, thereby stimulating protein kinase A to reduce [Ca 2+ ] i and promote relaxation (Drake et al 2000;Brain & Grant, 2004). The vasodilator actions of CGRP may be enhanced through it acting presynaptically on sympathetic nerve varicosities to inhibit NA release (Kawasaki et al 1990b;Takenaga & Kawasaki, 1999).…”

Section: Diminished Influence Of Sensory Nerves On Sympathetic Vasocomentioning

confidence: 99%

Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo

Westcott

Segal

2013

The Journal of Physiology

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Key points• Neural control of the circulation is integral to the regulation of tissue blood flow and systemic blood pressure. Vascular dysfunction occurs with ageing but little is known of corresponding changes in the role(s) of perivascular nerves.• We developed a preparation to study intact mesenteric arteries (MAs) in anaesthetized mice to investigate age-related changes in the function of perivascular sympathetic and sensory nerves in vivo.• Ageing decreased the diameter of MAs, reduced their sensitivity to α 1 -adrenoreceptor stimulation and impaired the ability of sensory nerves to attenuate sympathetic vasoconstriction.• These changes were manifest in males and females and were unaffected by the expression of the GCaMP2 transgene in endothelial cells, confirming the utility of this model.• Our results imply that ageing imposes structural and functional limitations to the splanchnic circulation that impair the ability to mobilize blood from the gut in times of physical stress.Abstract Mesenteric arteries (MAs) are studied widely in vitro but little is known of their reactivity in vivo. Transgenic animals have enabled Ca 2+ signalling to be studied in isolated MAs but the reactivity of these vessels in vivo is undefined. We tested the hypothesis that ageing alters MA reactivity to perivascular nerve stimulation (PNS) and adrenoreceptor (AR) activation during blood flow control. First-(1A), second-(2A) and third-order (3A) MAs of pentobarbital-anaesthetized Young (3-6 months) and Old (24-26 months) male and female Cx40 BAC -GCaMP2 transgenic mice (C57BL/6 background; positive or negative for the GCaMP2 transgene) were studied with intravital microscopy. A segment of jejunum was exteriorized and an MA network was superfused with physiological salt solution (pH 7.4, 37• C). Resting tone was ≤ 10% in MAs of Young and Old mice; diameters were ∼5% (1A), 20% (2A) and 40% (3A) smaller (P ≤ 0.05) in Old mice. Throughout MA networks, vasoconstriction increased with PNS frequency (1-16 Hz) but was ∼20% less in Young vs. Old mice (P ≤ 0.05) and was inhibited by tetrodotoxin (1 μM). Capsaicin (10 μM; to inhibit sensory nerves) enhanced MA constriction to PNS (P ≤ 0.05) by ∼20% in Young but not Old mice. Phenylephrine (an α 1 AR agonist) potency was greater in Young mice (P ≤ 0.05) with similar efficacy (∼60% constriction) across ages and MA branches. Constrictions to UK14304 (an α 2 AR agonist) were less (∼20%; P ≤ 0.05) and were unaffected by ageing. Irrespective of sex or transgene expression, ageing consistently reduced the sensitivity of MAs to α 1 AR vasoconstriction while blunting the attenuation of sympathetic vasoconstriction by sensory nerves. These findings imply substantive alterations in splanchnic blood flow control with ageing.

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“…either a CGRP receptor or an adrenomedullin receptor, depending on the RAMP expressed. The RAMP proteins appear to be multifunctional and are essential for the transport of the receptor from the endoplasmic reticulum to the cell surface, for specific glycosylation, for ligand binding specificity (McLatchie et al 1998, Fraser et al 1999 and possibly for receptor desensitization (Drake et al 1999(Drake et al , 2000. Furthermore, it appears that the RAMPs have a similar role in modulating the function of the CT-R as a receptor for calcitonin, amylin or CGRP (Muff et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Failed export of the adrenocorticotrophin receptor from the endoplasmic reticulum in non-adrenal cells: evidence in support of a requirement for a specific adrenal accessory factor

Noon¹,

Franklin²,

King³

et al. 2002

Journal of Endocrinology

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Difficulty in expressing the adrenocorticotrophin (ACTH) receptor (melanocortin 2 receptor; MC2R) after transfection of various MC2R expression vectors has been experienced by many researchers. Reproducible evidence for expression has been obtained only in the Y6/OS3 corticoadrenal cell lines or in cells expressing endogenous melanocortin receptors. In order to determine the cause of this failure of expression we have undertaken the following studies. An MC2R expression plasmid was constructed in which the green fluorescent protein (GFP) coding region had been added to the C-terminus of the mature protein. Transfection of this plasmid into Y6 cells with a cAMP-responsive reporter plasmid demonstrated normal function of this receptor. Imaging of CHO cells expressing MC2R-GFP revealed perinuclear expression, although a cholecystokinin receptor (CCKR)-GFP construct was efficiently expressed at the cell surface. Y6 cells, in contrast, showed cell surface fluorescence after transfection with MC2R-GFP. Several other cell types showed a similar pattern of GFP distribution characteristic of retention in the endoplasmic reticulum. Counterstaining with an anti-KDEL antibody confirmed this location. Coexpression of the MC2R and the CCKR-GFP did not impair CCKR trafficking to the cell surface, implying a receptor-specific impairment to trafficking in the CHO cell which was absent in the Y6 cell.

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Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

Cited by 21 publications

References 22 publications

Inhibitory actions of calcitonin gene‐related peptide and capsaicin: evidence for local axonal reflexes in the bladder wall

Inhibitory actions of calcitonin gene‐related peptide and capsaicin: evidence for local axonal reflexes in the bladder wall

Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo

Failed export of the adrenocorticotrophin receptor from the endoplasmic reticulum in non-adrenal cells: evidence in support of a requirement for a specific adrenal accessory factor

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