Two types of electrical activity are found in gut smooth muscle cells; they are slow waves which contribute to the basic electrical rhythm and spike potentials . Except for the esophagus and proximal stomach , most parts of the bowel have a spontaneous rhythmical fluctuation in resting membrane potential or slow waves, generally between −60 and −65 mV. This fluctuation represents an interval of cyclic depolarization followed by repolarization and is called the basic electrical rhythm (BER). The frequency of BER oscillations varies from one part of the bowel to another (Fig. 2.3), and depolarization is not necessarily accompanied by muscular contractions.

The origin of the BER appears to be specialized “pacemaker” cells (interstitial cells of Cajal). These stellate, muscle-like cells interconnect, have projections to muscle cells, and receive neural fibers from nearby myenteric plexuses. In the stomach and small intestine , they are located at the inner circular muscle layer, near the myenteric plexus. In the colon, dominant pacemaker cells appear to be located in the submucosal border of the circular muscle layer. As in the conduction system of the heart, dominant pacemakers, i.e. ones having greater cyclic frequency, capture and entrain subsidiary pacemakers. Thus, in any region of the gut, the electrical characteristics of the dominant regional pacemaker will be not only rapidly propagated circumferentially but also transmitted orad and aborad. However, a descending gradient of pacemaker frequency is known to exist in most regions of the gut, with the possible exception of the colon. Thus, when propagation of a pacemaker BER along the long axis of the gut weakens, more distal subsidiary pacemakers will assume the pacemaker role. Studies have suggested that an aboral ascending gradient may be present in the colon. As will be discussed below, this hierarchical arrangement in BER frequency in various regions of the gut may have important functional significance.

Because of the tight circumferential electrical coupling of smooth muscle cells, the BER propagation is extremely rapid and can also be measured in adjacent muscle cells in any given gut segment. The mechanism for generation of the BER is believed to be the consequence of a balance between the depolarizing inward flux of calcium through dihydropyridine-insensitive Ca²⁺ channels and the repolarizing efflux of K ⁺ from the cell through Ca²⁺-activated K⁺ channels (Fig. 2.3, insert). The cycle begins with the slow buildup of Ca²⁺ ions in the cell (a depolarizing process) that progressively inactivates further Ca²⁺ influx and simultaneously activates Ca²⁺-activated K⁺ channels, leading to K⁺ efflux (a repolarizing process).

Although depolarizations of the BER in stomach and colon can occasionally lead to small motor contractions, most contractions occur after rapid changes in membrane potential differences called spike potentials , which are superimposed on the depolarizing phase of the BER (Fig. 2.4). These “action potentials” are quite different from those seen in mammalian nerve or striated muscle. Their depolarizing phase is caused by the activation of Ca²⁺-dependent K⁺ channels or increased activity of nonselective cation or Cl⁻ channels. This is often initiated by stimulation of cells with excitatory ligands. The resulting influx of K⁺ depolarizes the cells, causing an activation of voltage dependent Ca²⁺ channels. However, this is only one component contributing to the observed increases in cytosolic Ca²⁺ necessary for producing muscular contraction. In circular muscle cells, the other component involves inositol 1,4,5-triphosphate (IP ₃ )-stimulated Ca ²⁺ release from intracellular stores, with IP₃ generated from ligand-stimulated hydrolysis of membrane phosphatidylinositol . In longitudinal muscle cells, IP₃ appears to have little role in activating increases in [Ca²⁺]_i. Little IP₃ is generated after ligand stimulation, and addition of IP₃ to permeabilized cells has little effect in releasing Ca²⁺, consistent with the lack of IP₃ receptors regulating internal calcium pools. In these cells, excitatory ligands appear to activate Cl⁻ channels, depolarizing the cells and stimulating the opening of voltage-sensitive Ca²⁺ channels. However, the end result in both circular and longitudinal muscles may be the same. Initial increases in cytosolic calcium augment additional and more sustained increases through the activation of plasma membrane or sarcoplasmic Ca²⁺ channels.

Stimulated increases in Ca²⁺ are required for electromechanical coupling. This explains why not all phases of smooth muscle BER are associated with contraction. Even at the peak of membrane depolarization, if the threshold potential for initiating these events is not achieved, contraction will not occur. Spike potentials superimposed on phasic BER depolarization increase the probability that the threshold potential will be reached (Fig. 2.5). The appearance and frequency of spike potentials are greatly affected by hormonal agents and neurotransmitters. The greater the number of spike potentials per BER cycle, the greater is the degree of muscular contraction. Epinephrine , for example, markedly decreases spike potentials and inhibits contraction, whereas acetylcholine stimulates them and promotes contraction. The major function of the BER, therefore, is to dictate when contractions can occur in a certain area in the bowel. Its basic rhythm does not appear to be affected by hormones and neurotransmitters. If there are no spike potentials, contractions will generally not occur. On the other hand, if an agent promotes numerous spike potentials, the frequency of muscular contractions cannot exceed that of the BER.

How do stimulated increases in cytosolic Ca²⁺ cause contraction of smooth muscles? Increased cytosolic Ca²⁺ binds to the calcium-regulatory protein calmodulin, forming a complex that activates myosin light chain kinase (MLC kinase) (Fig. 2.6). MLC kinase stimulates the phosphorylation of myosin, a critical step in initiating the actin-myosin interaction essential for muscular contraction. Protein kinase C, activated through the generation of diacylglycerol, also appears to have a role, especially in maintaining the duration of contraction.

Relaxation of smooth muscles involves restoration of basal Ca ²⁺ levels, decreased MLC kinase activity, and commensurate increase in MLC phosphatase action. Several mechanisms appear to be involved in decreasing cytosolic Ca²⁺, including the activation of Ca²⁺-ATPase to pump Ca²⁺ out of the cells or back into internal Ca²⁺ stores. In addition, repolarization of the plasma membrane inhibits further entry of Ca²⁺ via voltage-activated calcium channels. MLC phosphatase causes the dephosphorylatioin of myosin, with cessation of the actin-myosin interaction.

Inhibitory agents generally work by stimulating increases in cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), secondary messengers that appear to counteract the effects of increased cytolic Ca²⁺ in several ways. For example, the stimulation of cAMP- and cGMP-dependent protein kinases have been shown to inhibit IP₃ formation and its effects on Ca²⁺ release from internal calcium stores. These kinases may also stimulate mechanisms involved in the re-uptake or lowering of cytosolic calcium, including stimulation of Ca²⁺-ATPase of plasma membrane or cellular organelles. As a third mechanism, increases in cyclic nucleotides may play a role in stimulatory mechanism, such as Ca²⁺-dependent K⁺ channels, which repolarize the cell and inhibit the actions of excitatory stimuli. Inhibitory agents that stimulate increases in smooth muscle cell cAMP include vasoactive intestinal peptide (VIP), glucagon , and peptide histidine isoleucine (PHI) or peptide leucine methionine (PHM), in humans. Nitric oxide is inhibitory because it stimulates soluble guanylate cyclase and increased cellular cGMP levels.

Most excitatory agents of intestinal motility work by stimulating increases in cytosolic Ca ²⁺ and/or inhibiting the formation of cyclic nucleotides. For instance, acetylcholine ’s excitatory actions are mediated by muscarinic receptor-stimulated increases in cytosolic Ca²⁺. Other agents such as μ- and δ-opioid receptor agonists also inhibit adenylate cyclase activity, in addition to stimulating increases in cytosolic Ca²⁺. Serotonin (5-hydroxytryptamine, 5-HT), on the other hand, simultaneously stimulates increases in cytosolic Ca²⁺ through 5-HT₂ receptors and increases in adenylate cyclase activity and cAMP via stimulation of 5-HT₄ receptors. These seemingly counterproductive actions probably serve as a form of cellular feedback regulation.

Other regulatory agents of intestinal motility act indirectly, either by stimulating or inhibiting the release of other neuropeptides or hormones. As an example of this modulatory role, cholecystokinin (CCK) and bombesin stimulate intestinal motility by enhancing the release of excitatory peptides such as acetylcholine and substance P. By contrast, neuropeptide Y and somatostatin inhibit the release of these agents. As another layer of complexity, agents such as somatostatin can further inhibit motility by inhibiting the release of opioid peptides that normally would inhibit VIP release of nitric oxide production. The net effect, therefore, is decreased inhibitory tone on release of VIP secretion, causing inhibition of motility.