Substance P is essential for maintaining gut muscle contractility

A novel role for coneurotransmission revealed by botulinum toxin

Cuiping Li, Maria Micci, Karnam S. Murthy, Pankaj Jay Pasricha

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Substance P (SP is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A, a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and by measuring phosphorylation of myosin light chain 20 (MLC20. BoNT/A (10 IU significantly reduced the response of pyloric muscle to exogenous ACh, an effect that was accompanied by reduced MLC20 phosphorylation in the muscle. Both effects were reversed by exogenous SP. CP-96345, a NK1 receptor antagonist, blocked the ability of exogenous SP to reverse the cholinergic hyporesponsiveness as well as the reduction in MLC20 phosphorylation induced by BoNT/A. In conclusion, we have identified a novel role for SP as a coneurotransmitter that appears to be important for the maintenance of muscular responsiveness to the principal excitatory neurotransmitter, ACh. These results also provide new insight into the effects of botulinum toxin on the enteric nervous system and gastrointestinal smooth muscle.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume306
Issue number10
DOIs
StatePublished - May 15 2014

Fingerprint

Botulinum Toxins
Substance P
Muscles
Neurotransmitter Agents
Pylorus
Phosphorylation
Smooth Muscle
Enteric Nervous System
Myosin Light Chains
Motor Neurons
Neuropeptides
Baths
Cholinergic Agents
Maintenance
incobotulinumtoxinA

Keywords

  • Acetylcholine
  • Botulinum toxin
  • Cholinergic responsiveness
  • Coneurotransmission
  • Gut smooth muscle contractility
  • MLC phosphorylation
  • Substance P

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology
  • Hepatology
  • Gastroenterology

Cite this

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title = "Substance P is essential for maintaining gut muscle contractility: A novel role for coneurotransmission revealed by botulinum toxin",
abstract = "Substance P (SP is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A, a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and by measuring phosphorylation of myosin light chain 20 (MLC20. BoNT/A (10 IU significantly reduced the response of pyloric muscle to exogenous ACh, an effect that was accompanied by reduced MLC20 phosphorylation in the muscle. Both effects were reversed by exogenous SP. CP-96345, a NK1 receptor antagonist, blocked the ability of exogenous SP to reverse the cholinergic hyporesponsiveness as well as the reduction in MLC20 phosphorylation induced by BoNT/A. In conclusion, we have identified a novel role for SP as a coneurotransmitter that appears to be important for the maintenance of muscular responsiveness to the principal excitatory neurotransmitter, ACh. These results also provide new insight into the effects of botulinum toxin on the enteric nervous system and gastrointestinal smooth muscle.",
keywords = "Acetylcholine, Botulinum toxin, Cholinergic responsiveness, Coneurotransmission, Gut smooth muscle contractility, MLC phosphorylation, Substance P",
author = "Cuiping Li and Maria Micci and Murthy, {Karnam S.} and Pasricha, {Pankaj Jay}",
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T2 - A novel role for coneurotransmission revealed by botulinum toxin

AU - Li, Cuiping

AU - Micci, Maria

AU - Murthy, Karnam S.

AU - Pasricha, Pankaj Jay

PY - 2014/5/15

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N2 - Substance P (SP is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A, a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and by measuring phosphorylation of myosin light chain 20 (MLC20. BoNT/A (10 IU significantly reduced the response of pyloric muscle to exogenous ACh, an effect that was accompanied by reduced MLC20 phosphorylation in the muscle. Both effects were reversed by exogenous SP. CP-96345, a NK1 receptor antagonist, blocked the ability of exogenous SP to reverse the cholinergic hyporesponsiveness as well as the reduction in MLC20 phosphorylation induced by BoNT/A. In conclusion, we have identified a novel role for SP as a coneurotransmitter that appears to be important for the maintenance of muscular responsiveness to the principal excitatory neurotransmitter, ACh. These results also provide new insight into the effects of botulinum toxin on the enteric nervous system and gastrointestinal smooth muscle.

AB - Substance P (SP is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A, a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and by measuring phosphorylation of myosin light chain 20 (MLC20. BoNT/A (10 IU significantly reduced the response of pyloric muscle to exogenous ACh, an effect that was accompanied by reduced MLC20 phosphorylation in the muscle. Both effects were reversed by exogenous SP. CP-96345, a NK1 receptor antagonist, blocked the ability of exogenous SP to reverse the cholinergic hyporesponsiveness as well as the reduction in MLC20 phosphorylation induced by BoNT/A. In conclusion, we have identified a novel role for SP as a coneurotransmitter that appears to be important for the maintenance of muscular responsiveness to the principal excitatory neurotransmitter, ACh. These results also provide new insight into the effects of botulinum toxin on the enteric nervous system and gastrointestinal smooth muscle.

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