Nonselective cation channels (NSCCs) are defined as the channel exhibiting better selectivity for cations over anions. This nomenclature is however confusing, because the channels which fall into this category show a high degree of heterogeneity in their biophysics, physiology and pharmacology. Since little molecular information is yet available for most types of NSCC (except for the fast extracellular ligand-gated NSCC), one useful criterion to sub-classify them is the mode of activation. Based on this, more than 10 subclasses of NSCC, including the G-protein-coupled NSCC as a newly emerging member, can be distinguished (Table 1). Furthermore, the biophysical and pharmacological profile of these subclasses of NSCC suggest that varying extents of structural similarities may exist. Such a duality, i.e. heterogeneity and similarity of NSCC is on one hand, the obstacle to exploiting selective drugs for NSCCs, but on the other hand, may account for a broad repertoire of functions that NSCCs subserve under various patho-physiological conditions. This short paper briefly overviews, from such an aspect, the physiology and pharmacology of NSCCs of the plasma membrane, which have rather poorly been elucidated so far.

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Some competitive antagonists, which produce effects opposite to those of agonist (inverse agonism), are recently called inverse agonists. New evidence suggests a two-state model in which G-protein-coupled receptors are in equilibrium between the inactive conformation (R) and a spontaneously active conformation (R^*) in the absence of classic agonists. Classic agonists have a high affinity for R*, whereas inverse agonists (negative antagonists) have a high affinity for R and decrease the concentration of R^*. Neutral competitive antagonists have equal affinity for both types, R and R^* and do not displace the equilibrium, but can competitively antagonize the effects of agonists and of inverse agonists. The inverse agonists may be useful in clinic.

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The role of cholinergic nerves in the regulation of the motility of the sphincter of Oddi (SO) has been investigated by cholinergic stimulation and blockade, but their result may be a composite of effects on multiple cholinergic neural and neuromuscular transmissions and reflex pathways. We used botulinum toxin that selectively blocks cholinergic nerves within the area of local injections to study the role of its cholinergic innervation. Four conscious dogs with a duodenal cannula underwent manometry of the common bile duct, SO, and duodenum. After baseline recording, each dog had intrasphincteric injections of saline or botulinum toxin, and the manometry was repeated on day 7. The injections of botulinum toxin caused a significant decrease in the mean SO basal pressure from 6.6±0.1 mmHg to 3.6±0.2 mmHg (p<0.0001) and amplitude from 47±2.5 mmHg to 29.2±1.6 mmHg (p<0.0001), but no change in the frequency of the SO phasic contractions and temporal coordina-tion of SO cyclic motility and the duodenal migrating motor complex. The saline injections had no effect on the SO basal pressure, amplitude, frequency, and cyclic motility. These results indicate that cholinergic nerves play an important role in maintaining the SO basal pressure and amplitude but do not contribute to the cyclic changes in its motility in phase with the duodenal migrating motor complex. Botulinum toxin would be a useful tool to study the effect of the cholinergic innervation. Key words: sphincter of Oddi, migrating motor complex, botulinum toxin, cholinergic innervation.

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