Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress G-protein-coupled inward rectifier (GIRK) channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and the nucleus tuberomammillaris (TM) were used, as well as HEK293A cells transfected with GIRK1 and 2, either human orexin receptor type 1 (OX1R) or type 2 (OX2R), mu opioid receptor and GFP cDNAs. In GTPgammaS-loaded cells, orexin A (OXA, 3 microM) inhibited GIRK currents that had previously been activated by somatostatin (in LC cells), nociceptin (TM cells), or the mu opioid agonist DAMGO (HEK cells). In guanosine triphosphate (GTP)-loaded HEK cells, in which GIRK currents were not preactivated, OXA induced a biphasic response through both types of orexin receptors: an initial current increase and a subsequent decrease to below resting levels. Current-voltage (I-V) relationships revealed that both the OXA-induced and suppressed currents are inwardly rectifying with reversal potentials around EK. The OXA-induced initial current was partially pertussis toxin (PTX) sensitive and partially PTX insensitive, whereas the OXA-suppressed current was PTX insensitive. These data suggest that orexin receptors couple with more than one type of G-protein, including PTX-sensitive (such as Gi/o) and PTX-insensitive (such as Gq/11) G-proteins. The modulation of GIRK channels by orexins may be one of the cellular mechanisms for the regulation of brain nuclei (e.g., LC and TM) that are crucial for arousal, sleep, and appetite.
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PMID:Effects of orexin (hypocretin) on GIRK channels. 1270 4

Although it is established that neurokinin B is expressed by some neurons in laminae I-III of the rat spinal dorsal horn, little is known about the proportions of cells in these laminae that express neurokinin B, or whether these are excitatory or inhibitory neurons. Neurokinin B is derived from preprotachykinin B, and we have used an antibody against preprotachykinin B to address these issues. We found that preprotachykinin B-immunoreactive neurons were present throughout laminae I-III, constituting 10-11% of the neuronal population in laminae I-II, and 4% of that in lamina III. They formed a prominent band in the ventral half of lamina II (where they made up 16% of the population) and the dorsalmost part of lamina III. The great majority (99%) of preprotachykinin B-immunoreactive axonal boutons contained the vesicular glutamate transporter 2, while none contained glutamic acid decarboxylase. Since most of these boutons are likely to be derived from local preprotachykinin B-expressing cells, these observations suggest that most of the latter are excitatory interneurons. Although 9% of preprotachykinin B-labeled axonal varicosities were substance P-immunoreactive, none contained calcitonin gene-related peptide, which is consistent with reports that neurokinin B is not expressed by primary afferent axons. Many of the preprotachykinin B-immunoreactive cells contained compounds that are present in putative excitatory neurons in laminae I-III: calbindin (84%), protein kinase Cgamma (76%) or somatostatin (31%). However, there was little or no overlap between preprotachykinin B and three other markers associated with excitatory neurons in these laminae: the mu opioid receptor MOR-1, the neurokinin 1 receptor and neurotensin. These results suggest that neurokinin B is expressed by specific populations of excitatory neurons in the superficial dorsal horn. By examining expression of Fos protein in response to intraplantar injection of formaldehyde we provide evidence that many of the preprotachykinin B cells in lamina I and the outer part of lamina II respond to noxious stimulation.
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PMID:Characterization of neurons that express preprotachykinin B in the dorsal horn of the rat spinal cord. 1644 41

In the rat dentate gyrus, mu opioid receptor (MOR) agonists disinhibit principal cells, promoting excitation, but whether MOR protein is differentially distributed to interneuron subtypes is unknown. Here, the distribution of MOR immunoreactivity was semi-quantitatively examined in neurochemically identified interneurons using fluorescence microscopy. We find that MOR- and parvalbumin-immunoreactivities are frequently co-localized, while MOR- and somatostatin-immunoreactivities are less commonly co-localized. This suggests that MORs are most frequently on interneurons specialized to inhibit granule cell output, and are on a limited number of interneurons that inhibit granule cell distal dendrites.
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PMID:Mu opioid receptors are extensively co-localized with parvalbumin, but not somatostatin, in the dentate gyrus. 1671 8

Frequent oncogenic alterations occur in the phosphoinositide 3-kinase (PI3K) pathway, urging identification of novel negative controls. We previously reported an original mechanism for restraining PI3K activity, controlled by the somatostatin G protein-coupled receptor (GPCR) sst2 and involving a ligand-regulated interaction between sst2 with the PI3K regulatory p85 subunit. We here identify the scaffolding protein filamin A (FLNA) as a critical player regulating the dynamic of this complex. A preexisting sst2-p85 complex, which was shown to account for a significant basal PI3K activity in the absence of ligand, is disrupted upon sst2 activation. FLNA was here identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switching of GPCR binding preference from p85 toward FLNA is determined by changes in the tyrosine phosphorylation of p85- and FLNA-binding sites on sst2 upon activation. It results in the disruption of the sst2-p85 complex and the subsequent inhibition of PI3K. Knocking down FLNA expression, or abrogating FLNA recruitment to sst2, reversed the inhibition of PI3K and of tumor growth induced by sst2. Importantly, we report that this FLNA inhibitory control on PI3K can be generalized to another GPCR, the mu opioid receptor, thereby providing an unprecedented mechanism underlying GPCR-negative control on PI3K.
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PMID:A switch of G protein-coupled receptor binding preference from phosphoinositide 3-kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway. 2220 38


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