ARE JUNCTION POTENTIALS ESSENTIAL? DUAL MECHANISM OF SMOOTH MUSCLE CELL ACTIVATION BY TRANSMITTER RELEASED FROM AUTONOMIC NERVES (1986)

Stimulation of autonomic nerves supplying smooth muscle tissues often evokes either an e.j.p. or an i.j.p. which involves a shift in the membrane potential such that the entry of calcium into the cell through voltage‐sensitive calcium channels is likely to be increased or decreased respectively. In smooth muscle which freely discharges action potentials either spontaneously or in response to excitatory influences in vivo, the change in membrane potential will alter the rate of action potential discharge and so the tension developed by the smooth muscle. In this way there is modulation of the rate of entry of calcium, or its release within the cell, by a voltage‐dependent mechanism entrained by the junction potential, as the action potential represents the operation of voltage‐dependent calcium channels. In smooth muscles not freely discharging action potentials, the numbers of open calcium channels may change with depolarization, or even hyperpolarization, so the junction potential again brings into play a voltage‐dependent mechanism of calcium entry. However, a dual mechanism of neurotransmission seems to operate at many autonomic nerve‐smooth muscle junctions such that voltage‐independent mechanisms coexist with voltage‐dependent mechanisms. It is now generally accepted that activation of receptors on smooth muscle cells caused by bathing smooth muscles in solutions containing excitatory transmitters can bring into operation processes which are not voltage‐dependent and which do not depend on modulation of the rate of action potential discharge. Up to the present it has been by no means certain that when released from autonomic nerves these excitatory transmitters (ACh, noradrenaline, substance P and n.a.n.c. excitatory transmitters) could also act in the same voltage‐independent way ‐ not least because studies of smooth muscle cells at the cellular level have been dominated by membrane potential recording (by micro‐electrode) which has revealed the e.j.p. or some form of depolarization as a seemingly ubiquitous feature of excitatory autonomic junctions of nerve and smooth muscle cells. However, experiments show that under conditions when the e.j.p. and/or the action potential are abolished or severely impaired by drug application, substantial nerve‐evoked smooth muscle contractions may occur at many autonomic junctions. Conversely, severe impairment of nerve‐evoked contraction may occur in some cases with excitatory‐receptor antagonists without loss, or even in some cases any impairment, of the e.j.p. which presumably depends on a different receptor type: in these cases either the transmitter evoking the e.j.p. is different to that which is mainly responsible for evoking contraction, or if both e.j.p. and contraction are evoked by the same substance, then different receptor subtypes seem to be involved. In the case of inhibitory transmitters the evidence is less extensive. It seems likely, however, that voltage‐independent mechanisms are also involved. There is again ample evidence, for example, in the case of β‐adrenoreceptors, that their activation by bathing the muscle in an agonist inhibits tension by means of mechanisms which do not depend on a change in membrane potential and that β‐receptors can also be activated by nerve‐released noradrenaline. In the case of nerve‐released transmitters, the negligible change in membrane potential which occurs in some smooth muscles implies that a voltage‐independent mechanism is brought into play. Activation of receptors for n.a.n.c. transmitters (possibly more than one) as well as β‐adrenoreceptors, cause biochemical changes: a rise in cyclic GMP and in cyclic AMP levels occurring in these cases. How rises in these nucleotides are related to inhibition of tension is still obscure, however, but it seems likely that they do not occur simply as a consequence of any small change in membrane potential which might occur. It would seem that many, perhaps all, autonomic nerve‐smooth muscle junctions possess mechanisms of neurotransmission which are either electrically silent or in which the electrical changes are unimportant, and that these voltage‐independent mechanisms reinforce or synergize with the voltage‐dependent mechanisms entrained by the e.j.p. and the i.j.p.