Autonomic neuromuscular junctions
Graphical abstract
Depicted are the earliest images of smooth muscle cells (Kölliker 1854), Cajal's image of the bundling of smooth muscle cells (Cajal 1933), and a superimposed image or the terminal axons that innervate smooth muscle bundles.
Introduction
This review is a tribute to the significant contributions of Geoff Burnstock to our understanding of the ways in which autonomic neurons innervate and control smooth muscle. The junction between neurons and skeletal muscle, the motor end-plate, is well defined both anatomically and physiologically. Each skeletal muscle cell is innervated at a single point and every time an action potential arrives transmitter is released to cause a post-synaptic event, the end plate potential (e.p.p.). The e.p.p. always depolarises the muscle cell sufficiently to trigger an action potential and a subsequent contraction occurs every time an action potential arrives. This was well established by the 1950s.
Structural studies failed to identify similar discrete sites of innervation of smooth muscle. In the 1960s, Burnstock and Holman sought, for the first time, to apply intracellular microelectrodes to investigate the functional relationships between autonomic neurons and smooth muscle. This is the 60th anniversary year of their first major publication on the electrophysiology of neural transmission to smooth muscle. They investigated the vas deferens, a richly innervated smooth muscle organ that receives only an excitatory innervation (Burnstock and Holman, 1961; Burnstock and Holman, 1963). They discovered that nerve stimulation caused electrical events in the muscle, but that the events were much slower than e.p.p.'s, they usually did not cause muscle action potentials, and, unlike e.p.p.'s, their amplitudes were graded with stimulus strength. Burnstock and Holman were aware of the lack of evidence for specialised synapses in smooth muscle, so they avoided using the term synapse and instead introduced the term, Excitatory Junction Potential (EJP) to describe the events. Hyperpolarising events were later recorded and called Inhibitory Junction Potentials (IJPs). These were recorded in the muscle of the gastrointestinal tract in response to local stimulation of intramural nerves (Bennett et al., 1966). Burnstock later reviewed structural and physiological studies that led to a realistic model of what he named the autonomic neuromuscular junction (Burnstock, 2004). We have omitted from this review the important relationships between autonomic motor neurons and cardiac muscle.
The present review concentrates on electrical events (EJPs and IJPs) that occur in smooth muscle when neurons innervating the muscle are stimulated, because these events can be readily recorded in the muscle. However, it is clear that at many autonomic neuromuscular connections, post-junctional effects are mediated without a change in membrane potential (Muir and Wardle, 1988). In these cases, the coupling between cells allows propagation of second messenger signals. An example of a neurotransmitter whose action does not depend on a membrane potential change is nitric oxide (NO). NO is an inhibitory neurotransmitter in the gastrointestinal tract that diffuses across the smooth muscle cell membrane and activates soluble guanylate cyclase, thereby increasing levels of cyclic GMP, which relaxes the muscle by reducing cytoplasmic Ca2+ availability to the contractile apparatus (Young et al., 1993; Esplugues, 2002).
Section snippets
Structure of smooth muscle and its innervation
The cell theory, that all organisms are composed of individual cells, was proposed in 1838 for plants by Matthias Schleiden and in 1839 for animals by Theodor Schwann. The quest to investigate the cellular basis for tissue structure was taken up by Kölliker, who was puzzled whether the artery wall, and smooth muscle in general, that appeared solid, was made up of individual cells. He dissociated various organs and in 1847 found smooth muscles to be composed of individual fusiform cells with a
Electrical coupling in smooth muscle
The electrical connections between smooth muscle cells cause strips of smooth muscle, in which the long axes of the muscle cells are aligned, to behave like an electrical cable, although a rather leaky one (Abe and Tomita, 1968). Thus, if an electrical current is injected into the smooth muscle cells at one place along the bundle, then microelectrodes in muscle cells record a change in membrane potential at greater than a muscle cell length from the stimulus, consistent with current spreading
Asymmetrical innervation, especially of arterial smooth muscle
As mentioned above, several smooth muscle tissues have asymmetrical innervation. This is notable for arteries, where the innervation is concentrated at the external surface of the vessels, the medial-adventitial border (Nilsson et al., 1986; Burnstock, 2004); see Fig. 3.
The smooth muscle cells of arteries appear to be well coupled electrically. In small arteries within the intestinal wall that have only a single layer of smooth muscle cells, the length constant has been determined to be 1.1 to
Interstitial cells and neuromuscular control
The smooth muscle walls of the stomach and intestine, but not the smooth muscle of the urinary bladder, have within them interstitial cells with pacemaker properties, the interstitial cells of Cajal (Gabella, 2012) as well as other ICC-like cells that regulate smooth muscle activity (Sanders et al., 2016). The walls of the stomach and urinary bladder are similarly thick and in both cases the walls can change dimensions substantially to accommodate big changes in the amount of content of the
Summation of influence of multiple axons
Burnstock and Holman in their pioneering study (1961) found that varying the strength of stimulation changed the amplitudes of EJPs that were recorded by intracellular microelectrodes, which they concluded was a result of stimuli of different strengths recruiting different numbers of motor axons. Because some of these axons would be remote, and others close to the cell that was impaled, each axon is predicted to contribute different amounts to junctional events. In the mouse vas deferens, it
Discussion
In the years since the discoveries that smooth muscle is composed of many thousands of individual miniscule spindle-shaped cells (Kölliker, 1854) and that the axons that innervate smooth muscle branch and weave in the tissue so that they approach many smooth muscle cells (Cajal, 1895), a great deal more has been learnt, especially about the functional relationships between autonomic motor neurons and smooth muscle. Critical to this understanding was the pioneering of methods to record
Acknowledgements
We are indebted to Dr. James Brock, Professor Giorgio Gabella and Dr. Robin McAllen for insightful comments and discussion that have significantly improved the manuscript. We thank Cecile Castellano for the provision of the micrograph of Fig. 2C. This work was supported by NIH grant, The Virtual Stomach (1OT2OD030538), Principal Investigators Leo Cheng (University of Auckland) and Zhongming Liu (University of Michigan).
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