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Dynamics of inhibitory co-transmission, membrane potential and pacemaker activity determine neuromyogenic function in the rat colon

  • Organ physiology
  • Published:
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Abstract

Interaction of different neuromyogenic mechanisms determines colonic motility. In rats, cyclic depolarizations and slow waves generate myogenic contractions of low frequency (LF) and high frequency (HF), respectively. Interstitial cells of Cajal (ICC) located near the submuscular plexus (SMP) generate slow waves. Inhibitory junction potential (IJP) consists on a purinergic fast (IJPf) followed by a nitrergic slow (IJPs) component leading to relaxation. In the present study, we characterized (1) the dynamics of purinergic-nitrergic inhibitory co-transmission and (2) its contribution on prolonged inhibition of myogenic activity. Different protocols of electrical field stimulation (EFS) under different pharmacological conditions were performed to characterize electrophysiological and mechanical responses. Smooth muscle cells (SMCs) in tissue devoid of ICC-SMP had a resting membrane potential (RMP) of −40.7 ± 0.7 mV. Single pulse protocols increased purinergic and nitrergic IJP amplitude in a voltage-dependent manner (IJPfMAX = −26.4 ± 0.6 mV, IJPsMAX = −6.7 ± 0.3 mV). Trains at increasing frequencies enhanced nitrergic (k = 0.8 ± 0.2 s, IJPs∞ = −15 ± 0.5 mV) whereas they attenuated purinergic responses (k = 3.4 ± 0.6 s,IJPf∞ = −8.9 ± 0.6 mV). In tissues with intact ICC-SMP, the RMP was −50.0 ± 0.9 mV and nifedipine insensitive slow waves (10.1 ± 2.0 mV, 10.3 ± 0.5 cpm) were recorded. In these cells, (1) nitrergic and purinergic responses were reduced and (2) slow waves maintained their intrinsic frequency and increased their amplitude under nerve-mediated hyperpolarization. Based on the co-transmission process and consistent with the expected results on RMP, prolonged EFS caused a progressive reduction of LF contractions whereas HF contractions were partially insensitive. In conclusion, inhibitory neurons modulate colonic spontaneous motility and the principles determining post-junctional responses are (1) the frequency of firing that determines the neurotransmitter/receptor involved, (2) the transwall gradient and (3) the origin and nature of each myogenic activity.

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Abbreviations

ADPβS:

Adenosine 5′-Ο-2-thiodiphosphate

β-NAD:

β-Nicotinamide adenine dinucleotide

CO:

Carbon monoxide

EFS:

Electrical field stimulation

ENS:

Enteric nervous system

HF:

High frequency

ICC:

Interstitial cells of Cajal

IJP:

Inhibitory junction potential

KO:

Knockout

LF:

Low frequency

L-NNA:

N ω-Nitro-l-arginine

MRS2500:

(1R,2S,4S,5S)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicycle [3.1.0]hexane-1-methanol dihydrogen phosphate ester diammonium salt

NANC:

Non-adrenergic non-cholinergic

NO:

Nitric oxide

NOS:

Nitric oxide synthase

ODQ:

Oxadiazolo[4,3-α]quinoxalin-1-one

PDGRFα + cells:

Fibroblast-like cells

RMP:

Resting membrane potential

SEM:

Standard error of the mean

SMC:

Smooth muscle cell

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Acknowledgments

We thank Claudia Arenas, Antonio Acosta and Emma Martínez for their technical assistance.

Conflict of interest

This work has been funded by the following grant: BFU2009-11118 and 2011 CTP 00032. Noemí Mañé (AP2012-0897), Víctor Gil (AP2007-01583) and Míriam Martínez-Cutillas (AP2010-2224) are supported by the Ministerio de Ciencia e Innovación (Spain). Diana Gallego is supported by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en red de enfermedades hepáticas y digestivas (CIBERehd). The authors state no conflict of interest.

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Authors and Affiliations

  1. Department of Cell Biology, Physiology and Immunology and Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

    Noemí Mañé, Víctor Gil, Míriam Martínez-Cutillas, María Teresa Martín, Diana Gallego & Marcel Jiménez

  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Barcelona, Spain

    Diana Gallego & Marcel Jiménez

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  1. Noemí Mañé
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  2. Víctor Gil
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Correspondence to Marcel Jiménez.

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Mañé, N., Gil, V., Martínez-Cutillas, M. et al. Dynamics of inhibitory co-transmission, membrane potential and pacemaker activity determine neuromyogenic function in the rat colon. Pflugers Arch - Eur J Physiol 466, 2305–2321 (2014). https://doi.org/10.1007/s00424-014-1500-8

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