PubMed · 8035169
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J R Cooper. 1994. Unsolved problems in the cholinergic nervous system.. https://doi.org/10.1046/j.1471-4159.1994.63020395.x
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Excess salt loads in most non-mammalian vertebrates are dealt with by a variety of extra-renal salt-secreting structures collectively described as salt glands. The best studied of these are the supra-orbital nasal salt glands of birds. Two distinct types of response to osmoregulatory disturbances are shown by this structure: a progressive adaptive response on initial exposure to a salt load that results in the induction and enhancement of the secretory performance or capabilities of the gland; and the rapid activation of existing osmoregulatory mechanisms in the adapted gland in response to immediate osmoregulatory imbalance. Not only is the time-frame of these two types of response very different, but the responses usually involve fundamentally different processes: e.g., the growth and differentiation of osmoregulatory structures and their components in the former case, compared with the rapid activation of ion channels, pumps etc. in the latter. Despite marked differences in the nature and time-frame of these responses, they both are apparently triggered by neuronally released acetylcholine, which acts at muscarinic receptors on the secretory cells to induce an inositol phosphate-dependent increase in cytosolic-free calcium concentrations ([Ca2+]i). Therefore, the question arises as to how the cells produce the appropriate distinct response using a single common signal (i.e., an increase in [Ca2+]i). Examination of the features of this signaling pathway in the two conditions described, reveals that they each are uniquely tuned to generate a response with the characteristics appropriate for the cells' requirements. This tuning of the signal involves often rather subtle changes in the overall signaling pathway that are part of the adaptive differentiation process.
The effects of dynorphin A (1-13), a kappa-opioid receptor agonist, on the content of acetylcholine (ACh) and high K+-induced release of endogenous ACh were studied in mice exposed to carbon monoxide (CO). Mice were exposed to CO 3 times at 1-hr intervals and used 7 days after CO exposure. Administration of dynorphin A (1-13) (1.5 and 5.0 nmol/mouse, intracerebroventricularly) 15 min before killing significantly increased the ACh content in the striatum and hippocampus of control mice, but had no effect on the ACh content in CO-exposed mice. Dynorphin A (1-13) did not change the choline acetyltransferase (EC 2.3.1.6) activity in control or CO-exposed mice. The high K+-induced endogenous ACh release from hippocampal slices in CO-exposed mice was significantly lower than that of controls, although exposure to CO did not affect the basal release of endogenous ACh from hippocampal slices compared with controls. Dynorphin A (1-13) caused dose-dependent decreases in high K+-induced release of endogenous ACh from hippocampal slices in control mice. This inhibitory effect of dynorphin A (1-13) was blocked by co-perfusion with nor-binaltorphimine, a selective K-opioid receptor antagonist. On the other hand, dynorphin A (1-13) did not decrease high K+-induced release of endogenous ACh from hippocampal slices in CO-exposed mice. These results suggest that dysfunction of the cholinergic system occurred after exposure to CO, and as a result the inhibitory effects of dynorphin A (1-13) may be blocked in CO-exposed mice.
1. G protein-gated K+ channels (KACh channels) in the heart and brain are activated by the betagamma subunit of inhibitory G protein. Phosphatidylinositol-4,5-bisphosphate (PIP2) has recently been reported to directly activate KACh channels (GIRK) expressed in oocytes, as well as to support activation by the betagamma subunit in the presence of Na+. We examined the effect of Na+, PIP2 and other phospholipids on the KACh channel to understand better their role in KACh channel activation and modulation. 2. In atrial membrane patches, none of the phospholipids tested including PIP2 caused activation of the KACh channel in either the presence or the absence of 30 mM Na+. PIP2 (3 microM) and other phospholipids (30 microM) blocked acetylcholine-induced activation of the KACh channel. 3. When KACh channels were first activated with GTPgammaS, however, all phospholipids (100 microM) tested augmented the KACh channel activity 1.5- to 2-fold. Phosphatidylinositol-4-phosphate (PIP) and PIP2 were an order of magnitude more potent than other phospholipids. The increase in KACh channel activity was the result of a shift in the gating mode of the channel from a short-lived to a longer-lived open state. Such a modulatory effect was qualitatively similar to that produced by intracellular ATP. Trypsin blocked the ATP effect but not the phospholipid effect on the KACh channel kinetics. 4. The phosphate group linked to the glycerol backbone was important for KACh channel modulation by phospholipids. The higher potency of PIP and PIP2 was due to the presence of inositol phosphates. 5. Intracellular Na+ (30 mM) increased the frequency of KACh channel opening approximately 2-fold if the channels were already active, but did not affect modulation by phospholipids. The effects of Na+ and phospholipids on KACh channel activity were additive. 6. A low concentration of ATP (20 microM), which had no effect on the KACh channel by itself, potentiated the stimulatory action of phospholipids, indicating that ATP and phospholipids interacted to modulate KACh channel function. 7. We conclude that exogenously applied PIP2 and other phospholipids block agonist-mediated KACh channel activation. However, if the KACh channel is already activated with GTPgammaS, phospholipids augment the existing activity by increasing the number of longer-lived channel openings. The evidence for and against the role of PIP and PIP2 in the stimulatory effect of ATP on the KACh channel is presented and discussed.