Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the preceding paper (Kramer and Levitan, 1988), we presented evidence that an inwardly rectifying K+ current (IR) is inactivated by Ca2+ influx accompanying spontaneous bursting activity in the Aplysia neuron R15. In this paper we examine the mechanism that enables Ca2+ to inactivate IR. Since IR is enhanced by cyclic AMP in neuron R15 (Drummond et al., 1980; Benson and Levitan, 1983), we examined the Ca2+-dependent inactivation of IR after application of either serotonin (5-HT), the adenylate cyclase activator forskolin, or a membrane-permeable cAMP analog, all agents that increase cAMP and hence the magnitude of IR. Even though more active IR channels are available under these conditions, less Ca2+-dependent inactivation is observed. This is contrasted with the Ca2+-dependent inactivation of the voltage-gated Ca2+ current (ICa). Elevating cAMP enhances ICa in R15 and also increases its Ca2+-dependent inactivation. Hence the mechanisms whereby Ca2+ inactivates IR and ICa appear to differ from each other. Elevating internal Ca2+ by repeatedly depolarizing the neuron suppresses the response of IR to brief applications of 5-HT, and speeds the relaxation of the response, suggesting that Ca2+ can interfere with the cAMP-dependent activation of IR. One biochemical site where Ca2+ can reduce cellular cAMP is by activating the Ca2+/calmodulin-sensitive form of phosphodiesterase. We have detected such enzyme activity in homogenates of Aplysia abdominal ganglia and extracts of single R15 somata. Inhibitors of the phosphodiesterase activity suppress the Ca2+-dependent inactivation of IR. Finally, we have used a radioimmunoassay to measure cAMP in individual R15 somata, and have found that R15 neurons hyperpolarized for prolonged periods contain more cAMP than do R15 neurons allowed to burst, consistent with the hypothesis that Ca2+ influx reduces cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Mechanism of calcium-dependent inactivation of a potassium current in Aplysia neuron R15: interaction between calcium and cyclic AMP. 283 52

Cultured neurons from the CA1 and CA3 regions of the rat hippocampus were studied by using the whole-cell version of patch clamp. Application of acetylcholine (5-10 microM) or muscarine (20 microM) to a neuron with a holding potential of approximately -70 mV produced a slow inward current. This inward current was inhibited by atropine (1-2 microM). Loading the cell with GTP gamma S caused a change in the muscarinic response. In the control cells the muscarine-induced inward current recovered by 89%. On the other hand, in the GTP gamma S-loaded cells the inward current recovered by only 30%, indicating some irreversibility. Pertussis toxin treatment did not change the muscarine-induced slow inward current. Loading the cells with cyclic AMP (100 microM) plus IBMX (1 mM) (an inhibitor of phosphodiesterase) did not occlude the effect of muscarine. We conclude that the slow inward current is mediated through a pertussis toxin-insensitive G protein, and that cyclic AMP is not a part of the signal transduction cascade. The finding that the GTP gamma S-loaded cells did not show complete irreversibility was discussed in relation to the results of Benson et al. (J. Physiol., 404 (1988) 479-496), which showed that there are two ionic mechanisms responsible for the muscarine-induced depolarization. Occasionally cells were encountered, in which muscarine (or acetylcholine) evoked a large and rapid inward current, followed by the usual slow inward current. The time course of this rapid response was not affected by GTP gamma S.
 ...
PMID:The role of G protein in muscarinic depolarization near resting potential in cultured hippocampal neurons. 839 28