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The contractile behaviour of gastrointestinal smooth muscles is dependent on the intrinsic electrical activities of the muscles.1 Depolarisation activates L-type Ca2+channels that provide the main pathway for Ca2+ to enter gastrointestinal smooth muscle cells. This is particularly true for the phasic portions of the gastrointestinal tract where cyclic depolarisations and repolarisations, referred to as slow waves, set the contractile frequency and maintain the phasic nature of contractions (fig 1). The slow wave cycle ensures a period of relaxation between contractions, allowing mixing and movement of luminal contents. Tonic regions of the gastrointestinal tract, such as the sphincters, are also regulated by electrical events but primarily by more persistent changes in resting membrane potential.
In addition to the ionic conductances that contribute to resting membrane potential and electrical rhythmicity, there are several ionic conductances that are modulated by neural and hormonal inputs. Regulatory inputs from nerves, hormones, and paracrine substances are superimposed on the spontaneous electrical activity of gastrointestinal muscles. Electrical responses to biologically active substances result from: (i) modulation of ionic conductances that are already active and going through dynamic changes in open probability during the slow wave cycle; and (ii) activation of agonist dependent conductances that do not participate in basal electrical activity. Ca2+ entry into smooth muscles is mainly controlled by rather subtle changes in the open probability of L-type Ca2+channels.2 3 The more frequently these channels open and the longer they stay open, the more major their influence on cytoplasmic Ca2+. Studies of ion channel regulation in gastrointestinal muscles have led to the general hypothesis that regulation of Ca2+ entry in gastrointestinal muscles is primarily accomplished by regulation of conductances other than L-type Ca2+ channels. In general, excitatory transmitters and hormones increase Na+ influx through non-selective cation channels (fig 2). The resulting depolarisation and elevation in slow wave amplitude increases the open probability of Ca2+channels. Inhibitory transmitters enhance the open probabilities of a variety of K+ channels (fig 3). Hyperpolarisation and reduced excitability decreases Ca2+ channel open probability. In excitatory and inhibitory neurotransmission, membrane potential appears to be the main factor regulating the open probability of L-type Ca2+ channels.
Stimulation of muscarinic receptors causes activation of non-selective cation channels in gastrointestinal muscles. This conductance has been observed and characterised in several species, and several generalisations are possible. Little or none of the non-selective cation current is available in unstimulated gastrointestinal muscles. The conductance is activated by receptor occupation and a pertussis toxin sensitive G protein, suggesting coupling through Gi/Go. 4 The conductance is facilitated by intracellular Ca2+. The single channel conductance appears to be 20–30 pS, and the channels are voltage dependent over the physiological range of potentials. A number of ions and drugs block this conductance (for example, Gd3+, Cd2+, Ni2+, quinine, and fenamates) but specific blockers have not been identified. Although the non-selective channels are permeable to Ca2+, they conduct very little Ca2+ in physiological ionic gradients. Stimulation of tachykinin receptors also activates a non-selective cation conductance. However, the channels responsible appear to be distinct from those activated by muscarinic stimulation, as the tachykinin induced current is not facilitated by Ca2+ and currents activated by the two agonists summate.5 The non-selective cation conductances are nearly equally permeable to Na+ and K+ and the current produced by the conductance reverses at approximately 0 mV. As gastrointestinal muscle cells operate at potentials negative to 0 mV, the net current through non-selective cation channels is always inward and carried predominantly by Na+ ions. Entry of Na+ has no known effect on the contractile process, but the depolarisation caused by entry of positive charge increases the open probability of Ca2+channels.
A variety of inhibitory transmitters and hormones elicit responses via enhanced production of cyclic adenosine monophosphate (cAMP). These include noradrenaline, vasoactive intestinal peptide, pituitary activating cyclic AMP peptide P, adenosine (P1 receptors), and secretin. cAMP produces paradoxical effects on L-type Ca2+currents, in that cAMP dependent mechanisms enhance Ca2+current in smooth muscle myocytes.6 This effect is likely to be due to phosphorylation by cAMP dependent protein kinase A, which is known to increase Ca2+ current in heart and other tissues.7 This trend, which would tend to make agonists that use cAMP dependent pathways excitatory, is counteracted in gastrointestinal muscles by concomitant activation of a variety of K+ channels. Activation of K+ channels limits excitability and decreases the open probability of Ca2+channels. The types of K+ channels expressed and utilised in cAMP dependent responses vary in different species and in different parts of the gastrointestinal tract. We know at least that ATP dependent K+ channels,8 large conductance (BK) Ca2+ activated K+ channels,9 15 pS delayed rectifier K+ channels, and 90 pS voltage dependent K+ 10 can be activated in gastrointestinal muscle cells by cAMP dependent mechanisms. Other channels, such as an inward rectifier K+ channel, may also be regulated by cAMP dependent mechanisms and contribute to the changes in resting potential noted in response to agonists that enhance cAMP. Nitric oxide and cyclic guanosine monophosphate dependent mechanisms are also coupled to activation of several types of K+ channels, some of which are discrete from the channels activated by cAMP.11
Electrical mechanisms are supplemented and further regulated by release and uptake of Ca2+ from stores. Release of Ca2+from stores can sum with Ca2+ entry to increase cytoplasmic levels but a more subtle form of regulation has also been described. Many of the conductances involved in electrical rhythmicity and agonist responses are sensitive to intracellular Ca2+,9 so localised changes in Ca2+ near the membrane can significantly influence open probability. Recent studies have demonstrated that fundamental Ca2+ release events from stores (Ca2+ sparks) regulate the open probabilities of Ca2+ dependent channels.12 Small conductance Ca2+ activated K+ channels have been found to mediate responses to ATP, another enteric inhibitory neurotransmitter, and these channels may be regulated primarily by Ca2+ release from stores.13 14 Modulating uptake and release of Ca2+ offers an important regulatory control on spark activity and the open probabilities of Ca2+ dependent channels.
There is growing evidence that neural inputs to the muscular components of the gastrointestinal tract are mediated, in part, via interstitial cells of Cajal (ICC).15 It will be important in future studies to compare the relative responsiveness of ICC and smooth muscle cells. It is anticipated that specific receptors, second messengers, and/or ion channels may be expressed to a greater extent by ICC. It is also possible that the mechanisms for transducing signals from neurotransmitters are equally expressed by smooth muscle cells and ICC, but the close proximity of ICC to varicose nerve terminals causes these cells to experience much higher concentrations of neurotransmitter substances. Studies to delineate these questions await identification of the classes of ICC thought to mediate neurotransmission and comparative studies between ICC and smooth muscle cells.
- Abbreviations used in this paper:
- interstitial cells of Cajal
- cyclic adenosine monophosphate
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