Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relatively little is known about physiological regulators of hypothalamic beta-endorphin (END) secretion and mechanisms by which they stimulate secretion. We sought to determine whether activation of the cyclic AMP (cAMP) second messenger pathway was involved in stimulating hypothalamic beta-END secretion from dissociated fetal hypothalamic cells in culture. Forskolin (FSK), a direct activator of adenylate cyclase which stimulates cAMP formation, stimulated immunoreactive (IR)-beta-END secretion. Because FSK can also stimulate independent of increased cAMP formation, we studied dibutyryl cAMP and 8-bromo-cAMP, analogues of cAMP, which also stimulated IR-beta-END secretion. From these studies we conclude: (1) activation of the cAMP second messenger system stimulates IR-beta-END secretion from hypothalamic cells and supports the rationale that endogenous regulators which stimulate this pathway could be involved in the physiological regulation of hypothalamic beta-END secretion; (2) coupling between the cAMP second messenger pathway and stimulation of hypothalamic beta-END secretion which is presumably present at maturity (adulthood) originates at early stages of development (fetal life).
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PMID:Activation of cyclic AMP second messenger system stimulates secretion of beta-endorphin from fetal hypothalamic cells. 131 2

Long-term regulation of mammalian steroid hormone synthesis occurs principally by transcriptional regulation of the gene for the rate-limiting cholesterol side-chain cleavage enzyme P450scc. Adrenal steroidogenesis is regulated primarily by two hormones: adrenocorticotropin, which works via cyclic AMP (cAMP) and protein kinase A, and angiotensin II, which works via Ca2+ and protein kinase C. Forskolin and 8-bromo-cAMP stimulated, while prolonged treatment with a phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA]) and a calcium ionophore (A23187) additively suppressed accumulation of endogenous P450scc mRNA in transformed murine adrenal Y1 cells. In Y1 cells transfected with 2,327 base pairs of the human P450scc promoter fused to the bacterial gene for chloramphenicol acetyltransferase (CAT), forskolin increased CAT activity 900% while combined TPA plus A23187 reduced CAT activity to 15% of the control level. Forskolin induced the P450scc promoter as rapidly as a promoter containing two cAMP-responsive elements fused to a simian virus 40 promoter, a system known to respond directly to cAMP. Basal expression was increased by sequences between -89 and -152 and was increased further by sequences between -605 and -2327. This upstream region also conferred inducibility by cAMP. TPA plus A23187 transiently increased CAT activity before repressing it, reflecting the complex actions of angiotensin II in vivo. Repression by prolonged treatment with TPA plus A23187 was mediated by multiple elements between -89 and -343. Induction of CAT activity by forskolin was not diminished by treatment with TPA plus A23187, nor were the regions of the promoter responsible for regulation by the two pathways coisolated. Thus, the human gene for P450scc is repressed by TPA plus A23187 by mechanisms and sequences independent of those that mediate induction by cAMP.
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PMID:Human P450scc gene transcription is induced by cyclic AMP and repressed by 12-O-tetradecanoylphorbol-13-acetate and A23187 through independent cis elements. 170 Feb 77

Forskolin-resistant mutants arise from Y1 mouse adrenocortical tumor cells with a frequency indicative of a mutational event at a single genetic locus and exhibit adenylyl cyclases that are resistant to activation by forskolin, corticotropin, and guanyl-5'-yl-imidodiphosphate. This study examined the levels of guanyl nucleotide-binding regulatory protein subunits (G) in plasma membranes from the forskolin-resistant mutants by Western blot immunoanalysis. In plasma membranes prepared from parental Y1 cells and from four forskolin-resistant mutants, 10r-2, 10r-3, 10r-6, and 10r-9, the levels of the alpha-subunits of Gs and Gi-2 were reduced by 70-80% relative to the levels in parental Y1 cells. The levels of the beta 36-subunit were much less affected, and the levels of the alpha i-3 and beta 35-subunits varied independently of the forskolin-resistant phenotype. As determined by slot blot hybridization analyses, the levels of Gs alpha and Gi alpha RNA in the forskolin-resistant mutants were equivalent to those in the Y1 parent. Therefore, the decreased levels of Gs alpha and Gi alpha-2 subunits observed in the forskolin-resistant mutants did not result from decreased expression of the genes encoding these proteins. Our observations suggest that the forskolin-resistant phenotype of Y1 mutants resulted from single mutations that affected the processing of specific G alpha subunits or their incorporation into the plasma membrane.
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PMID:Decreased levels of guanyl nucleotide-binding regulatory protein alpha-subunits in Y1 adrenocortical tumor cell mutants resistant to forskolin. 170 99

The direct effects of hydrocortisone (HS) and adrenocorticotropin (ACTH) on testicular testosterone production were studied in purified immature pig Leydig cells in vitro. Leydig cells were obtained from 3- to 4-week-old piglet testes by enzymatical dispersion followed by discontinuous Percoll gradient centrifugation. Leydig cells were treated with HS and ACTH in the absence or presence of luteinizing hormone (LH) after 12 h of incubation. Media were collected 48 h later for testosterone and cyclic adenosine 3',5'-monophosphate (cAMP) measurement. Treatment of Leydig cells with increasing concentrations (0.001-10.0 micrograms/ml) of HS for 48 h resulted in a dose-dependent increase in basal and LH-stimulated testosterone production. Increasing duration (6-72 h) of treatment with HS (100 ng/ml) led to a time-dependent increase in basal and LH-stimulated testosterone production, achieving statistical significance by 48 and 24 h, respectively. HS increased LH-stimulated cAMP production. HS also increased testosterone production induced by (Bu)2 cAMP. Forskolin stimulated testosterone production to an extent comparable to that attained with LH, and HS augmented forskolin-stimulated testosterone production. HS enhanced the conversion of exogenous 17 alpha-hydroxyprogesterone to testosterone, but did not affect the conversion of pregnenolone and progesterone to testosterone, suggesting a specific stimulation of 17,20-desmolase. Porcine ACTH had no influence on basal and LH-stimulated testosterone production. These results suggest that HS directly stimulates immature pig Leydig cell steroidogenesis, at least in part via an enhancement of the generation of cAMP, leading to an increase in the activity of 17,20-desmolase.
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PMID:Effect of cortisol on testosterone production by immature pig Leydig cells. 184 43

The authors examined the effect of topical application of agents known to increase cyclic nucleotide levels on tear secretion by accessory lacrimal gland tissue in their rabbit model for keratoconjunctivitis sicca (KCS). Tear secretion was studied by changes in tear film osmolarity and tear volume caused by application of the agents relative to application of isotonic buffer solution alone. A decrease in tear film osmolarity or increase in tear volume was interpreted as an increase in tear secretion. Irritative stimulation was distinguished from pharmacologic stimulation by the prior use of topical proparacaine. The following agents significantly decreased tear film osmolarity and increased tear volume: vasoactive intestinal peptide (2 X 10(-8) to 2 X 10(-6) M); three pro-opiomelanocortin fragments alpha-, beta-, and gamma-melanocyte stimulating hormone at 10(-4), 10(-3), and 10(-3) M, respectively; the permeable cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) analogs 8-Br cAMP (0.3-3.0 X 10(-3) M) and 8-Br cGMP (1.0-10.0 X 10(-3) M); and the cyclic nucleotide phosphodiesterase inhibitor 1-isobutyl-3-methyl xanthine (0.3-3.0 X 10(-3) M). Forskolin (2 X 10(-4) M), which activates the catalytic subunits of adenyl cyclase, increased tear volume significantly. Secretin, adrenocorticotropic hormone, and pilocarpine were ineffective. The authors conclude that agents that increase either cAMP or cGMP levels pharmacologically stimulated tear secretion when applied topically to rabbit eyes with surgically induced KCS.
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PMID:Stimulation of tear secretion by topical agents that increase cyclic nucleotide levels. 236 69

Intracellular recordings from primary mechanosensory neurones (dorsal cells) in the lamprey spinal cord were used to test the membrane effects of a variety of putative neuromodulatory agents. gamma-Aminobutyric acid (GABA) produced a dose-dependent increase in the duration of mixed Na-Ca or pure Ca action potentials in these cells. L-Glutamate and glycine produced minimal broadening of Ca action potentials. Acetylcholine, noradrenaline, serotonin, met-enkephalin, D-glutamate and dopamine had no effect. The pharmacology of GABA's action appeared to be complex. While the GABAA receptor antagonists, bicuculline, picrotoxin and curare, did not block GABA's effect, both the GABAA receptor agonist, muscimol, and the GABAB-receptor agonist, baclofen, occasionally broadened Ca action potentials in these cells. GABA had no effect on the resting potential, passive current-voltage (I-V) characteristics and pure Na action potential of dorsal cells, ruling out an action on passive membrane channels, transmitter-activated channels, or on those voltage-dependent channels activated during the Na action potential. Thus, GABA affected dorsal cells only when a significant Ca current was evident. GABA appeared not to increase the conductance of the Ca channels since its action was accompanied by an increase in input resistance, suggesting an inhibition of Ca-dependent conductance that normally acts to repolarize the membrane during a Ca action potential. An inhibitory effect of GABA on a Ca-dependent Cl conductance was ruled out in experiments where the Cl gradient was altered by removal of extracellular Cl without affecting GABA-induced Ca action potential prolongation. Dorsal cells have a prominent Ca-dependent K conductance (gK(Ca], and it is this conductance that GABA may inhibit. Consistent with this was the observation that the hyperpolarizing after-potential that follows Ca action potentials in dorsal cells, which reflects gK(Ca) in these cells and whose duration is normally increased when the Ca action potential duration increases, was not prolonged when the Ca action potential was broadened by GABA. Further, the failure of GABA to prolong Ba action potentials was consistent with this proposed mechanism of action, since Ba apparently does not activate gK(Ca) in these cells. Forskolin, a specific adenylate cyclase activator, caused broadening of Ca action potentials in lamprey dorsal cells comparable in magnitude to that of GABA. Thus, an increase in intracellular cyclic AMP is a candidate for the intracellular mediator of GABA's effect on these cells.
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PMID:Prolongation of calcium action potentials by gamma-aminobutyric acid in primary sensory neurones of lamprey. 243 26

Cell surface ligand-receptor interactions play a central role in the regulation and expression of macrophage function. Included among these macrophage membrane receptors are the beta-adrenergic and opioid receptors. We studied the abilities of epinephrine, met-enkephalin, forskolin, and adenosine 3':5' cyclic monophosphate (cAMP) analogues to affect macrophage morphology, spreading, and adherence. Cell spreading was quantitated by measuring the perimeters of adherent cell images recorded by videomicroscopy. Epinephrine induced a dose-dependent decrease in macrophage spreading; at 10(-5) M epinephrine the mean perimeter was 10.4 +/- 0.3 microns in comparison to 15.0 +/- 1.0 microns for controls. The inhibition of spreading can be blocked by the antagonist propranolol. On the other hand, met-enkephalin induced a dose-dependent increase in macrophage spreading, with a perimeter of 18.5 +/- 1.0 microns at 10(-8) M. Since catecholamines and opioids are simultaneously released from chromaffin cells of the adrenal, we examined the combinative effects due to treatment with both ligands. When macrophages were exposed to 10(-5) M epinephrine and 10(-8) M met-enkephalin, cell morphology and spreading were indistinguishable from that due to 10(-5) M epinephrine alone. The epinephrine dose-response curve in the presence of 10(-8) M met-enkephalin was similar to that of epinephrine alone. The beta-adrenergic receptor is apparently capable of diminishing or abrogating the opioid receptor signal(s). These combinative and epinephrine-mediated effects may be at least partially accounted for by the action of cAMP. Forskolin and the cAMP analogues N6-2'-O-dibutyryladenosine 3':5' cyclic monophosphate (dbcAMP) and 8-bromoadenosine 3':5' cyclic monophosphate (Br-cAMP) affected cell morphology and spreading in the same fashion as epinephrine. These differences in morphology and spreading behavior were accompanied by changes in the distribution of F-actin, as judged by phalladicin staining and fluorescence microscopy. We suggest that cAMP and microfilaments play important roles in receptor-mediated neuroregulation of macrophage function.
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PMID:Combinative ligand-receptor interactions: effects of cAMP, epinephrine, and met-enkephalin on RAW264 macrophage morphology, spreading, adherence, and microfilaments. 253 24

Forskolin, an activator of adenylate cyclase, stimulates adrenocorticotropin (ACTH) release and increases proopiomelanocortin mRNA levels in anterior pituitary cells by enhancing cyclic AMP (cAMP)-dependent protein kinase activity. The phorbol ester phorbol 12-myristate 13-acetate (PMA) evokes these same responses from anterior pituitary cells by activating protein kinase C. Both protein kinases most likely induce their cellular effects by catalyzing the phosphorylation of specific proteins. To elucidate the mechanisms by which cAMP-dependent protein kinase and protein kinase C promote ACTH secretion and synthesis, the phosphoproteins regulated by forskolin and PMA were identified in the cell line AtT-20, which consists of a homogeneous population of corticotrophs. Phosphoproteins were analyzed in different subcellular fractions by two-dimensional polyacrylamide gel electrophoresis and autoradiography. Forskolin increased phosphate incorporation into two proteins in the cytoplasmic fraction of 24 kilodaltons (kd) (pI 6.8) and 40 kd (pI 5.8), two proteins in the plasma membrane fraction of 32 kd (pI 8.3) and 60 kd (pI 8), and one protein in the nuclear fraction of 20 kd (pI 8.7). Insertion of the inhibitor of cAMP-dependent protein kinase into the AtT-20 cells, using a liposome technique, blocked the rise in phosphate incorporation induced by forskolin. PMA also stimulated phosphate incorporation into proteins in AtT-20 cells. PMA increased the phosphorylation of three cytoplasmic proteins of 25 kd (pI 7.6), 40 kd (pI 5.8), and 40 kd (pI 8.1) as well as two membrane proteins of 32 kd (pI 8.3) and 60 kd (pI 8) and one nuclear protein of 20 kd (pI 6.3).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein phosphorylation induced by phorbol esters and cyclic AMP in anterior pituitary cells: possible role in adrenocorticotropin release and synthesis. 253 66

Photoaffinity labelling of MSH receptors on Anolis melanophores was used as a tool for studying the effects of catecholamines, calcium and forskolin on hormone-receptor interaction and receptor-adenylate cyclase coupling. Covalent attachment of photoreactive alpha-MSH to its receptor was suppressed in calcium-free buffer but was hardly influenced by catecholamines or forskolin. The longlasting signal generated by the covalent MSH-receptor complex was readily and reversibly abolished by adrenaline, noradrenaline, dopamine or clonidine or by the absence of calcium. The suppression of pigment dispersion by catecholamines was blocked by the simultaneous presence of yohimbine but not prazosin, indicating that the catecholamines antagonize the alpha-MSH signal by inhibitory action on the adenylate cyclase system through an alpha-2 receptor. Forskolin, which stimulates melanophores by direct action on the catalytic unit of the adenylate cyclase and at about the same speed as alpha-MSH, produced a slower and weaker response in the presence of noradrenaline. If MSH receptors were covalently labelled and then exposed to noradrenaline, the characteristics of the forskolin-induced response were identical to those of unlabelled cells that had not been exposed to noradrenaline. This may point to a partial restoration of receptor-adenylate cyclase coupling by forskolin. The results show that the longlasting stimulation of Anolis melanophores by photoaffinity labelling proceeds via a permanently stimulated adenylate-cyclase system whose coupling to the receptor depends on calcium and is abolished by alpha-2 receptor agonists. Calcium is also essential for hormone-receptor binding.
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PMID:Photoaffinity labelling of MSH receptors on Anolis melanophores: effects of catecholamines, calcium and forskolin. 286 Feb 47

The effects of forskolin on the regulation of steroidogenesis and growth were examined in the Y1 adrenocortical tumor cell line, and the roles of cAMP and cAMP-dependent protein kinase in these actions of forskolin were evaluated. Forskolin, like corticotropin, stimulated steroidogenesis 3-fold and inhibited growth by 90%. In mutants of the Y1 cell line harboring specific defects in cAMP-dependent protein kinase activity, the responses to forskolin were attenuated. The resistance of the protein kinase mutants to the diterpene was closely correlated with their resistance to corticotropin and with impaired responses of their protein kinases to cAMP. These results indicate that cAMP and cAMP-dependent protein kinase are obligatory components of forskolin's actions on Y1 adrenal cells. Forskolin, at concentrations which were approximately 100-times greater than those required to stimulate steroidogenesis, caused cAMP to accumulate. Apparently, only a small fraction of the cAMP generated in response to forskolin was required to stimulate steroidogenesis or inhibit growth.
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PMID:The roles of cAMP and cAMP-dependent protein kinase in forskolin's actions on Y1 adrenocortical tumor cells. 300 70


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