The isolated somata of neurons from the thoracic ganglia of the locust, Locusta migratoria, respond to pressure microapplication of gamma-aminobutyric acid (GABA) and acetylcholine. The acetylcholine ...receptors fall into two groups. ACh1 (activated by nicotine) and ACh2 (activated by muscarine). The GABA receptor and the ACh1 receptor differ in pharmacology from the known vertebrate receptors. The GABA receptor is insensitive to bicuculline and its salts up to a concentration of 10(-4) M. In contrast, bicuculline is a moderately potent, at least partially competitive antagonist of the ACh1 receptor-mediated response in the thoracic neuronal somata. These observations suggest that classical diagnostic compounds such as bicuculline may show greater cross-reactivity than hitherto suspected among the members of the superfamily of ligand-activated channels.
Previous work has shown that serotonin causes an increase in K+conductance in the identified Aplysia neuron R15. This response is mediated by cAMP-dependent protein phosphorylation. The results ...presented here show that the K+channel modulated by serotonin is an anomalous or inward rectifier (designated IR) that is present in R15 together with the three other distinct K+channels previously described for this cell. Several lines of evidence indicate that this inward rectifier is partially activated in the resting cell and is further activated by serotonin. Voltage clamp analysis of resting and serotonin-evoked membrane currents at various external K+concentrations shows that both currents have reversal potentials close to the potassium equilibrium potential, exhibit similar dependences in magnitude on external K+concentration, and display marked anomalous rectification. The effects of particular monovalent and divalent cations are also similar on the resting and serotonin-evoked currents. Rb+, Cs+, and Ba2+block both currents while Tl+can substitute for K+as a charge carrier and channel activator in both. These properties are characteristic of anomalous rectifiers in other systems. Furthermore, measurement of the voltage dependence of inactivation for the fast transient K+current shows that this current cannot account for the anomalously rectifying K+conductance in R15. The inward rectifier is therefore a separate current mediated by its own channels, the activity of which can be modulated by serotonin.
The pharmacology of the extrasynaptic nicotinic and muscarinic acetylcholine receptors of the isolated neuronal somata from locust thoracic ganglia and the voltage-dependence of the currents they ...activate are discussed.
Synaptic localization of gamma-aminobutyric acid type A (GABA(A)) receptors is a prerequisite for synaptic inhibitory function, but the mechanism by which different receptor subtypes are localized to ...postsynaptic sites is poorly understood. The gamma2 subunit and the postsynaptic clustering protein gephyrin are required for synaptic localization and function of major GABA(A) receptor subtypes. We now show that transgenic overexpression of the gamma3 subunit in gamma2 subunit-deficient mice restores benzodiazepine binding sites, benzodiazepine-modulated whole cell currents, and postsynaptic miniature currents, suggesting the formation of functional, postsynaptic receptors. Moreover, the gamma3 subunit can substitute for gamma2 in the formation of GABA(A) receptors that are synaptically clustered and colocalized with gephyrin in vivo. These clusters were formed even in brain regions devoid of endogenous gamma3 subunit, indicating that the factors present for clustering of gamma2 subunit-containing receptors are sufficient to cluster gamma3 subunit-containing receptors. The GABA(A) receptor and gephyrin-clustering properties of the ectopic gamma3 subunit were also observed for the endogenous gamma3 subunit, but only in the absence of the gamma2 subunit, suggesting that the gamma3 subunit is at a competitive disadvantage with the gamma2 subunit for clustering of postsynaptic GABA(A) receptors in wild-type mice.
The aim of this study was to define the biophysical properties contributed by the γ2 subunit to native single GABA A receptors.
Single-channel activity was recorded from neurones of wild-type ...(γ2+/+) mice and compared with that from mice which were heterozygous
(γ2+/â) or homozygous (γ2â/â) for a targeted disruption in the γ2 subunit gene of the GABA A receptor. Unitary currents were evoked by low concentrations of GABA (0.5â5 μM) in membrane patches from acutely isolated
dorsal root ganglion (DRG) neurones (postnatal day 0) and by 1 μM GABA in patches from embryonic hippocampal neurones which
were cultured for up to 3 weeks.
GABA A receptors from DRG and hippocampal neurones of γ2+/+ and γ2+/â mice displayed predominantly a conductance state of 28 pS
and less frequently 18 and 12 pS states. In γ2â/â mice, conductance states mainly of 12 pS and less frequently of 24 pS were
found.
The mean open duration of the 28 pS state in γ2+/+ GABA A receptors (1.5â2.6 ms) was substantially longer than for the 12 pS state of γ2â/â GABA A receptors (0.9â1.2 ms) at all GABA concentrations. For γ2+/+ and γ2â/â channels, the mean open duration was increased at
higher GABA concentrations.
Open duration frequency distributions of 28 and 12 pS receptors revealed the existence of at least three exponential components.
Components with short mean durations declined and components with long mean durations increased in relative frequency at higher
GABA concentration indicating at least two binding sites of GABA per 28 and 12 pS receptor.
Shut time frequency distributions revealed at least four exponential components of which two were identified as intraburst
components in 28 pS and one in 12 pS GABA A receptors.
The mean burst duration and the mean number of openings per burst increased in 28 and 12 pS GABA A receptors with increasing GABA concentration. At least two burst types were identified: simple bursts consisting of single
openings and complex bursts of five to six openings in 28 pS but only two to three openings in 12 pS GABA A receptors.
We conclude that the γ2 subunit enhances the efficacy of GABA by determining open conformations of high conductance and long
lifetime, and by prolonging the time receptors remain in the activated bursting state.
In patients with midgut neuroendocrine tumors that progressed during octreotide analogue therapy, the addition of
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Lu-Dotatate to octreotide resulted in an 18% response rate and a significantly ...higher rate of progression-free survival at 20 months than high-dose octreotide alone.
Neuroendocrine tumors of the midgut (which is defined as the jejunoileum and the proximal colon) commonly metastasize to the mesentery, peritoneum, and liver and are frequently associated with the carcinoid syndrome.
1
,
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Neuroendocrine tumors of the midgut represent the most common type of malignant gastrointestinal neuroendocrine tumors and are associated with 5-year survival rates of less than 50% among persons with metastatic disease.
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,
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First-line systemic therapy usually consists of a somatostatin analogue for control of both hormonal secretion and tumor growth.
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–
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With the exception of everolimus for the treatment of nonfunctional neuroendocrine tumors,
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no standard second-line systemic treatment . . .
The fossil record of crocodylians and their relatives (pseudosuchians) reveals a rich evolutionary history, prompting questions about causes of long-term decline to their present-day low ...biodiversity. We analyse climatic drivers of subsampled pseudosuchian biodiversity over their 250 million year history, using a comprehensive new data set. Biodiversity and environmental changes correlate strongly, with long-term decline of terrestrial taxa driven by decreasing temperatures in northern temperate regions, and biodiversity decreases at lower latitudes matching patterns of increasing aridification. However, there is no relationship between temperature and biodiversity for marine pseudosuchians, with sea-level change and post-extinction opportunism demonstrated to be more important drivers. A 'modern-type' latitudinal biodiversity gradient might have existed throughout pseudosuchian history, and range expansion towards the poles occurred during warm intervals. Although their fossil record suggests that current global warming might promote long-term increases in crocodylian biodiversity and geographic range, the 'balancing forces' of anthropogenic environmental degradation complicate future predictions.
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