Cholinergic control mechanisms for immunoreactive motilin release and motility in the canine duodenum

The relationship of immunoreactive (IR) motilin release from the duodenum to duodenal motility changes was investigated in anaesthetized dogs. Stimulation of one or both vagi at 5 or 15 Hz or field stimulation of intrinsic duodenal nerves produced Significant increases in duodenal vein IR motilin concentrations and accompanying increases in duodenal motility. However, only stimulation of both vagi at 15 Hz produced significant changes in peripheral venous concentrations of IR motilin. These occurred after a delay at a time when both the duodenum and the antrum were quiescent. Either hexamelhonium or atropine blocked IR motilin release induced by stimulation of intrinsic or extrinsic nerves while only atropine inhibited the release induced by intraarterial carbachol. The response stimulated by carbachol and blocked by atropine was tetroclotoxin insensitive and the muscarinic receptor involved was presumably located on a nonneural structure. The site sensitive to hexamethonium was presumably the neural pathway which terminated at the muscarinic receptor. Concomitant studies of duodenal motility responses to vagal and field stimulation suggested a conventional neural pathway with preganglionic cholinergic nerves in the vagus, postganglionic cholinergic nerves in the duodenum (activated by field stimulation) and a smooth muscle muscarinic receptor. Activation of antral motility by stimulation of the abdominal vagus or intraarterial carbachol injections to the antrum increased duodenal IR motilin release in the absence of duodenal motility. Thus activation of the intrinsic nerves which cross the pylorus initiated IR motilin release as well as inhibited duodenal motility. Aside from this motility-independent release there was a close correlation between increased duodenal motility and IR motilin release. These findings imply that the rise in endogenous IR motilin levels associated with the passage of the activity front of the migrating motor complex through the duodenum may be initiated by the combined effects of increased vagal activity and increased gastric and duodenal motor activity.

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Cholinergic control of canine antral immunoreactive gastrin release and motility

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-126 ◽

1982 ◽

Vol 60 (7) ◽

pp. 893-901 ◽

Cited By ~ 11

Author(s):

J. E. T. Fox ◽

E. E. Daniel ◽

J. Jury ◽

N. S. Track ◽

S. Chiu

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscarinic Receptor ◽

Muscle Cell ◽

Gastrin Release ◽

Field Stimulation ◽

Antral Motility ◽

Stimulation Of ◽

Extrinsic Nerves

We used acute anaesthetized dogs to investigate the role of cholinergic receptors in the relationship between antral immunoreactive (I) gastrin release and antral motility. Electrical stimulation of extrinsic nerves via the cervical vagus or the nerve of Latarjet appeared to increase I gastrin release and antral motility by separate pathways as blockade of muscarinic receptors, i.e., atropinization inhibited motility but did not alter I gastrin release. On the other hand, blockade of nicotinic receptors by hexamethonium treatment obliterated I gastrin release induced by stimulation of the extrinsic nerves but only reduced motility. Field stimulation of intrinsic nerves via serosal electrodes also increased both I gastrin release and local motility. Since hexamethonium treatment only slightly reduced both I gastrin release and motility and atropinization eliminated both during field stimulation, the presence of a muscarinic receptor in the final pathway for each is proposed.Atropine eliminated carhachol-induced I gastrin release and motility increases, even in the presence of nerve blockade by tetrodotoxin. This suggests that this muscarinic receptor is on the smooth muscle cell itself and possibly on the gastrin cell. However a proposed role of the somatostatin cell in controlling gastrin release is also consistent with these data.Thus, both an intrinsic cholinergic and a separate extrinsic noncholinergic pathway are involved in antral release of I gastrin but initiation of motility appears to involve a final common pathway terminating in a muscarinic receptor on the smooth muscle cell.

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Stimulation of phosphoinositide hydrolysis by muscarinic receptor activation in the rat olfactory bulb

Biochemical Pharmacology ◽

10.1016/0006-2952(93)90062-2 ◽

1993 ◽

Vol 45 (2) ◽

pp. 281-287 ◽

Cited By ~ 7

Author(s):

Maria C. Olianas ◽

Pierluigi Onali

Keyword(s):

Olfactory Bulb ◽

Muscarinic Receptor ◽

Receptor Activation ◽

Phosphoinositide Hydrolysis ◽

Stimulation Of

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Stimulation of acid secretion and phosphoinositol production by rat parietal cell muscarinic M2 receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1988.254.4.g622 ◽

1988 ◽

Vol 254 (4) ◽

pp. G622-G629

Author(s):

A. Pfeiffer ◽

H. Rochlitz ◽

A. Herz ◽

G. Paumgartner

Keyword(s):

Acid Secretion ◽

Muscarinic Receptor ◽

Inositol Phosphates ◽

Inositol Phosphate ◽

Receptor Activation ◽

Receptor Subtype ◽

Muscarinic Agonists ◽

Receptor System ◽

Drug Concentrations ◽

Stimulation Of

The muscarinic receptor system involved in hydrogen ion production by enriched rat gastric parietal cells was investigated. Muscarinic receptor density determined by [N-methyl-3H]scopolamine binding was 8,100/cell. The receptor appeared to be of the M2 muscarinic receptor subtype, since it had a low affinity (Kd, 189 nM) for the M1 receptor antagonist pirenzepine compared with atropine (Kd, 0.74 nM). Receptor activation by carbachol rapidly augmented levels of polyphosphoinositides, indicating an activation of a phospholipase C. The dose-response relations for the increase in inositol phosphates closely paralleled the binding of carbachol to muscarinic receptors with a Km of 17 microM. The inositol phosphate response was antagonized by pirenzepine with a Ki of 177 nM. The stimulation of inositol phosphate levels by carbachol correlated well with the stimulation of [14C]aminopyrine uptake, determined as an index of acid secretion. The muscarinic agonists oxotremorine, pilocarpine, and bethanechol elicited partial increases in inositol phosphates at maximal drug concentrations, and these partial increases correlated with their ability to stimulate [14C]aminopyrine uptake. These data indicate that inositol polyphosphates may be a second messenger of M2 receptors stimulating acid secretion.

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Differential regulation of cholecystokinin- and muscarinic-receptor-mediated phosphoinositide turnover in Flow 9000 cells

Biochemical Journal ◽

10.1042/bj2510625 ◽

1988 ◽

Vol 251 (3) ◽

pp. 625-630 ◽

Cited By ~ 8

Author(s):

W W Y Lo ◽

J Hughes

Keyword(s):

G Protein ◽

Muscarinic Receptor ◽

Feedback Inhibition ◽

Inositol Phosphate ◽

Binding Capacity ◽

Second Messenger ◽

Receptor Activation ◽

Maximal Response ◽

Muscarinic Agonist ◽

Stimulation Of

We have explored the hypothesis that the apparent greater efficiency of cholecystokinin (CCK-8) receptor-second messenger coupling compared with that of muscarinic receptor in Flow 9000 cells is due to differential feedback inhibitory control mechanisms. Pretreatment of Flow 9000 cells with the tumour-promoting protein kinase C (PKC)-activating agent 12-O-tetradecanoylphorbol 13-acetate (TPA) produced a time- and dose-dependent inhibition of CCK-8 and acetylcholine (ACh) stimulation of inositol phosphate production. The inhibition by TPA of ACh-induced PI (phosphoinositide) response involved reduction of the maximal response, but no change in the concentration of ACh required to evoke a half-maximal response. In contrast, TPA inhibition of CCK-8 responses could be overcome by increasing the CCK-8 concentrations. Flow 9000 cells pretreated with TPA exhibited a 52-68% reduction in [3H]quinuclidinyl benzilate ([3H]QNB) binding capacity, whereas [125I]CCK-8 binding was unchanged. In saponin-permeabilized Flow 9000 cells, TPA pretreatment had no effect on guanosine 5′-[gamma-thio]triphosphate (GTP[S])-induced inositol phosphate formation, indicating that G-protein linkage to phosphoinositidase C (PIC) was not affected. However, TPA significantly inhibited the potentiating effect of GTP[S] on CCK-8 and ACh activation of PI response, suggesting that the coupling between the receptors and the G-protein was impaired. The PKC-activator 1-oleoyl-2-acetylglycerol (OAG), a diacylglycerol analogue, also significantly reduced CCK-8 and ACh stimulation of inositol phosphate accumulation in these cells. Our results are consistent with the hypothesis that muscarinic activation of PI hydrolysis is subjected to rapid feedback inhibition via the 1,2-diacylglycerol-PKC pathway. CCK-receptor activation of PI turnover is modulated to a lesser extent, and this may partially explain apparent differences in the efficiency of receptor-second messenger coupling. It is proposed that TPA acting through PKC exerts its inhibitory action on muscarinic-agonist-mediated PI response mainly at the receptor level, whereas the inhibitory effect on CCK-8 response is at a site close to the receptor-G-protein coupling step.

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SFKs, Ras, and the classic MAPK pathway couple muscarinic receptor activation to increased Na-HCO3 cotransport activity in renal epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.5.f844 ◽

2001 ◽

Vol 280 (5) ◽

pp. F844-F850 ◽

Cited By ~ 14

Author(s):

R. Brooks Robey ◽

Ofelia S. Ruiz ◽

Jessica Baniqued ◽

Dolores Mahmud ◽

Doris Joy D. Espiritu ◽

...

Keyword(s):

Epithelial Cells ◽

Proximal Tubule ◽

Muscarinic Receptor ◽

Mapk Pathway ◽

Receptor Activation ◽

Cholinergic Stimulation ◽

Proximal Tubule Cells ◽

Renal Epithelial Cells ◽

Tubule Cells ◽

Stimulation Of

Cholinergic agents are known to affect the epithelial transport of H2O and electrolytes in the kidney. In proximal tubule cells, cholinergic agonists increase basolateral Na-HCO3 cotransport activity via M1 muscarinic receptor activation. The signaling intermediates that couple these G protein-coupled receptors to cotransporter activation, however, are not well defined. We therefore sought to identify distal effectors of muscarinic receptor activation that contribute to increased NBC activity in cultured proximal tubule cells. As demonstrated previously for acute CO2-regulated cotransport activity, we found that inhibitors of Src family kinases (SFKs) or the classic mitogen-activated protein kinase (MAPK) pathway prevented the stimulation of NBC activity by carbachol. The ability of carbachol to activate Src, as well as the proximal (Raf) and distal [extracellular signal-regulated kinases 1 and 2 (ERK1/2)] elements of the classic MAPK module, was compatible with these findings. Cholinergic stimulation of ERK1/2 activity was also completely prevented by overexpression of a dominant negative mutant of Ras (N17-Ras). Taken together, these findings suggest a requirement for the sequential activation of SFKs, Ras, and the classic MAPK pathway [Raf→MAPK/ERK kinase (MEK)→ERK]. These findings provide important insights into the molecular mechanisms underlying cholinergic regulation of NBC activity in renal epithelial cells. They also suggest a specific mechanism whereby cholinergic stimulation of the kidney can contribute to pH homeostasis.

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ACh release from horse airway cholinergic nerves: effects of stimulation intensity and muscle preload

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.264.3.l269 ◽

1993 ◽

Vol 264 (3) ◽

pp. L269-L275 ◽

Cited By ~ 4

Author(s):

Z. Wang ◽

N. E. Robinson ◽

M. Yu

Keyword(s):

Release Rate ◽

Electrical Field Stimulation ◽

Minor Effect ◽

Field Stimulation ◽

Cholinergic Nerves ◽

Ach Release ◽

Electrical Field ◽

Stimulation Parameters ◽

A Minor ◽

Stimulation Of

This study was conducted to determine the effects of stimulation parameters and muscle preload on acetylcholine (ACh) release induced by electrical field stimulation (EFS) of horse airway cholinergic nerves. Trachealis strip bundles were prepared and suspended in 2-ml tissue baths. The tissues were stimulated three to five times for 30 min each. Increasing frequency (0.5-16 Hz) and voltage (5-20 V) increased ACh release; increasing pulse duration (0.5-3 ms) had only a minor effect. Alterations in muscle preload (2-20 g) had no effect on ACh release. ACh release was fairly constant for up to five repeated stimulation periods with the same EFS parameters. Stimulation of the tissues for 15 min released the same amount of ACh as 30 min if the amount was expressed as picomoles per gram per minute, suggesting that ACh release rate was constant during the 30-min period of stimulation. Atropine (10(-6) M) potentiated the release of ACh four- to fivefold, presumably by removing the autoinhibitory effect of ACh on the cholinergic nerves. Tetrodotoxin (10(-6) M) abolished the EFS-induced ACh release.

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PHOSPHOLIPASE A2 ACTIVATION BY A MECHANISM SEPARATE TO THAT RESPONSIBLE FOR PHOSPHOLIPASE C STIMULATION IN ALPHA-THROMBIN-STIMULATED HUMAN PLATELETS

10.1055/s-0038-1644470 ◽

1987 ◽

Author(s):

Michael F Crouch ◽

Eduardo G Lapetina

Keyword(s):

Phosphatidic Acid ◽

Phospholipase A2 ◽

Phospholipase C ◽

Inositol Phosphates ◽

Receptor Activation ◽

Human Platelets ◽

Cell Surface Receptor ◽

Control Mechanisms ◽

Induced Aggregation ◽

Stimulation Of

The ability of cell surface receptor occupation to increase the activity of phospholipase A2 has been thought to be due to the prior activation of phospholipase C and an increase in the intracellular Ca2+ concentration. However, recent evidence from our and other laboratories has suggested that this may not be the case, but rather stimulation of phospholipase A2 may be under the control of separate receptor-activated events. We have investigated this further by comparing the ability of prostacyclin (PGI2) and epinephrine to alter platelet responses to thrombin and examining the resulting phospholipase A2 activities.Alpha-thrombin stimulated aggregation of human platelets, the formation of inositol phosphates and phosphatidic acid, mobilizaton of Ca2+ from internal stores and Ca2+ influx, protein phosporylation (47 kDa and 20 kDa) and arachidonic acid (AA) release. Each of these responses was partially inhibited by prostacyclin (PGI2) except that of AA release, which was abolished. In combination with epinephrine and PGI2, alpha-thrombin-induced aggregation, phosphatidic acid formation and protein phosphorylation were restored, but the release of AA only reached 50% of its control value. Epinephrine alone had no effect on any of these responses, either in the presence or absence of PGI2. Thus, alpha-thrombin-induced activation of phospholipase A2 is more sensitive to the effects of PGI2 than is phospholipase C, and supports the possibility that there are distinct control mechanisms for receptor activation of these enzymes. We are presently examining the role of Gs in the inhibition by PGI2 of platelet phospholipase A2 and of Gi in the thrombin stimulation of this enzyme

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Receptor-operated Ca2+ channels in gastric parietal cells: gastrin and carbachol induce Ca2+ influx in depleting intracellular Ca2+ stores

Biochemical Journal ◽

10.1042/bj2890117 ◽

1993 ◽

Vol 289 (1) ◽

pp. 117-124 ◽

Cited By ~ 10

Author(s):

S Roche ◽

J P Bali ◽

R Magous

Keyword(s):

Steady State ◽

Receptor Activation ◽

Parietal Cells ◽

The Other ◽

Bivalent Cation ◽

Gtp Binding ◽

Gastric Parietal Cells ◽

Type Receptor ◽

Ca2 Channels ◽

Stimulation Of

The mechanism whereby gastrin-type receptor and muscarinic M3-type receptor regulate free intracellular Ca2+ concentration ([Ca2+]i) was studied in rabbit gastric parietal cells stimulated by either gastrin or carbachol. Both agonists induced a biphasic [Ca2+]i response: a transient [Ca2+]i rise, followed by a sustained steady state depending on extracellular Ca2+. Gastrin and carbachol also caused a rapid and transient increase in Mn2+ influx (a tracer for bivalent-cation entry). Pre-stimulation of cells with one agonist drastically decreased both [Ca2+]i increase and Mn2+ influx induced by the other. Neither diltiazem nor pertussistoxin treatment had any effect on agonist-stimulated Mn2+ entry. Thapsigargin, a Ca(2+)-pump inhibitor, induced a biphasic [Ca2+]i increase, and enhanced the rate of Mn2+ entry. Preincubation of cells with thapsigargin inhibits the [Ca2+]i increase as well as Mn2+ entry stimulated by gastrin or by carbachol. Thapsigargin induced a weak but significant increase in Ins(1,4,5)P3 content, but this agent had no effect on the agonist-evoked Ins(1,4,5)P3 response. In permeabilized parietal cells, Ins(1,4,5)P3 and caffeine caused an immediate Ca2+ release from intracellular pools, followed by a reloading of Ca2+ pools which can be prevented in the presence of thapsigargin. We conclude that (i) gastrin and carbachol mobilize common Ca2+ intracellular stores, (ii) Ca2+ permeability secondary to receptor activation involves neither a voltage-sensitive Ca2+ channel nor a GTP-binding protein from the G1 family, and (iii) agonists regulate common Ca2+ channels in depleting intracellular Ca2+ stores.

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