Changes In Receptor Responsiveness Research Articles

Probing Allosteric Modulation of Membrane Receptor in the Native State by Data Mining-Integrated Tracking Microscopy

Probing Allosteric Modulation of Membrane Receptor in the Native State by Data Mining-Integrated Tracking Microscopy

Somatosensory scaffolding structures

Dynamic changes in somatosensory perception occur as a result of multiple signaling events. In many instances, over-activation of sensory receptors results in the desensitization and subsequent increased threshold for activation of receptors. In other cases, receptor sensitization can occur following tissue injury and/or inflammation. In both cases, signaling mechanisms that control alterations in receptor activities can significantly affect organism response to sensory stimuli, including thermal, mechanical, and chemical. Due to the homeostatic nature of somatosensory recognition, dynamic changes in receptor response can negatively affect an individual's way of life, as well as alert individuals to tissue damage. Here, we will focus on scaffolding structures that regulate somatosensory neuronal excitability.

Alterations in the cholinergic system after frontal cortical infarction in rat brain: Pharmacological magnetic resonance imaging of muscarinic receptor responsiveness and stereological analysis of cholinergic forebrain neurons

Vascular cognitive impairment has been related to dysfunction of the central cholinergic system. Studies exploring the putative relationship between vascular cognitive impairment and cholinergic dysfunction have largely been aimed at symptomatic cholinergic treatment rather than focusing on etiological and pathological factors. The present study characterizes chronic responses of the cholinergic system to focal cerebral infarction. Two separate experiments investigated changes in receptor responsiveness versus changes in cell number after photothrombotic infarction of the frontal cortex in rat brain. First, we conducted pharmacological magnetic resonance imaging (phMRI) together with pilocarpine injection to assess relative cerebral blood volume (CBV) responses related to cholinergic muscarinic receptor activation. PhMRI was conducted at 1 and 3weeks after photothrombotic infarction of either the left or right frontal cortex. Second, stereological assessment was performed on choline acetyltransferase (ChAT)-immunostained sections to determine cholinergic cell body count in several basal forebrain nuclei at 4weeks after infarction. Significant reductions in relative CBV responses were observed both inside the ischemic area at 1 and 3weeks, and in areas distant from the lesion at 3weeks after right-sided frontal cortical infarction. In contrast, cholinergic cell number remained unchanged. These results demonstrate that cholinergic receptor responsiveness may be significantly altered following cerebral infarction, while projecting cholinergic cells are preserved.

The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation.

Cdk5 is an endogenous kinase activated by the neuronal-specific protein p35 and implicated in multiple neuronal functions, including modulation of certain pain responses. We investigated whether Cdk5 could regulate ATP-gated P2X(3) receptors that are members of the family of membrane proteins expressed by sensory neurons to transduce nociception in baseline and chronic pain. To study the potential P2X(3) receptor modulation by Cdk5, we co-transfected rat P2X(3) receptors and Cdk5 into HEK cells and observed increased P2X(3) receptor serine phosphorylation together with downregulation of receptor currents only when these genes were transfected together with the gene of the Cdk5 activator p35. The changes in receptor responses were limited to depressed current amplitude as desensitization and recovery were not altered. Transfection of p35 with P2X(3) similarly downregulated receptor responses, suggesting that this phenomenon could be observed even with constitutive Cdk5. The present data indicate a novel target to express the action of Cdk5 on membrane proteins involved in pain perception.

The effect of in vitro aging on human lung fibroblast beta-adrenergic receptor density, coupling and response

Age-related changes in regulation of receptor response have been observed in several tissues and include regulation of beta-adrenergic receptor (beta-receptor) responses. The role of cellular aging in age-related changes in receptor response is not clear. We have examined the effect of aging in vitro on human fibroblast beta-receptor produce cells of early, middle and late stages corresponding to the following cumulative population doublings: 15–20, 35–45 and > 50, respectively. Fibroblast membrane beta-receptor responses to isoproterenol (ISO, 0.1 mM) did nor to differ between the three stages. Adenylate cyclase response to prostaglandin E 1 (PGE 1, 1 μM), guanosine triphosphate (GTP, 0.1 mM) and 5′-guanylimidodiphosphate (Gpp(NH)p. 0.1 mM) were also similar between the stages. Beta-receptor density (B max) was unaffected by in vitro aging. Beta-receptor agonist affinity, an indication of the capacity or beta-receptor coupling to the nucleotide binding protein (N s), was also unaffected by cell aging. These findings suggest that cellular aging in fibroblasts alone is not accompanied by changes in beta-receptor function.

Oscillatory muscarinic acetylcholine responses of Xenopus oocytes are desensitized by protein kinase C and sensitized by protein phosphatase 2B

The oscillatory current response to acetylcholine (ACh) in Xenopus laevis oocytes, mediated by endogenous muscarinic ACh receptors, is known to be mildly desensitized by repetitive ACh applications. Pretreatment of oocytes with staurosporine (an inhibitor of protein kinases) was found not only to abolish this desensitization but also to positively and progressively potentiate oscillatory ACh responses. This sensitization by staurosporine was suppressed by 12-O-tetradecanoylphorbol 13-acetate (an activator of protein kinase C). In staurosporine-untreated (control) oocytes, intracellularly injected calcineurin (an isozyme of Ca 2+/calmodulin-dependent protein phosphatase 2B) or Ca 2+ enhanced oscillatory ACh responses, while trifluoperazine (a calmodulin inhibitor) suppressed the ACh responses but did not affect oscillatory responses to intracellularly injected inositol 1,4,5-triphosphate. These results suggest that, as far as short-term changes in receptor responsiveness are concerned, endogenous muscarinic ACh receptors in Xenopus oocytes are desensitized by phosphorylation by protein kinase C and sensitized by dephosphorylation by Ca 2+/calmodulin-dependent protein phosphatase 2B.

Selective cross-tolerance to 5-HT 1A and 5-HT 2 receptor-mediated temperature and corticosterone responses

The repeated administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 3 mg/kg, twice daily for 14 days) significantly diminished hypothermia and corticosterone secretion induced by an acute challenge with the 5-HT 1A agonist 8-OH-DPAT (0.1 mg/kg) when compared to the responses in animals treated chronically with the solvent vehicle. In contrast, the chronic administration of 5-MeODMT did not alter the magnitude of hyperthermia or corticosterone secretion induced by the acute administration of MK-212 (1.0 mg/kg). The repeated administration of the 5-HT 2 agonist DOI (1.0 mg/kg, daily for 7 days) significantly reduced the increase in corticosterone, but not body temperature, produced by MK-212. Chronic treatment with DOI did not alter the hypothermia or increase in corticosterone secretion elicited by 8-OH-DPAT. These data are consistent with other evidence that these physiological effects of 8-OH-DPAT and MK-212 are mediated by 5-HT 1A and 5-HT 2 receptors, respectively. Thus, data presented in these studies are suggestive that the chronic administration of 5-MeODMT diminishes the responsiveness of 5-HT 1A receptor-mediated changes in body temperature and cortiscosterone secretion without altering the responses mediated by 5-HT 2 receptors. In contrast, the chronic administration of DOI selectively diminishes the magnitude of 5-HT 2 receptor-mediated changes in corticosterone secretion without affecting the responsiveness of those receptors involved in thermoregulatory responses. These selective changes in receptor responsiveness following the chronic administration of these 5-HT agonists further establishes the independence of 5-HT 1A and 5-HT 2 receptor-mediated pharmacological effects.

Changes in receptor response by the effect of disease on membrane fluidity

Currently, changes that occur in receptor function under (patho-) physiological conditions are being investigated. The molecular mechanisms causing the observed variations are largely unknown. It is suggested that the pivotal role of the fluidity of the membrane has been neglected in the literature. It is hypothesized that aberrations in receptor function in diseases that are associated with a concomitant mild oxidative stress can be explained by membrane wavering.

Human Fetal Adrenal Cell Responses to ACTH and Pituitary Extracts

Human fetal adrenal tissues were studied in dispersed cell suspensions prepared by collagenase digestion;triplicate aliquots were incubated for 2 hours; control cells were compared to cells stimulated with 3 dilutions of ACTH and compared to responses from cells stimulated with 3 dilutions of 2 fractions prepared from human pituitaries (“A” and “B”). Crude fraction A contained FSH, LH and TSH; B contained ACTH, MSH and other peptides. 4 specimens with single adrenal weights of 128 mg, 243 mg, 488 mg and 915 mg were studied. Incubation medium was analyzed for dehydroepiandrosterone sulfate (DHAS) and corticoids (C). Unstimulated C secretion was similar in all weights (137 ± 63 pg/ml/100,000 cells); DHAS secretion was variable but increased with increasing size (16 ng/ml to 56 ng/ml/100,000 cells). ACTH caused dose-related proportionate increases in both DHAS and C in all; pit. frx “A” gave greater DHAS responses than ACTH in the 243 mg adrenal: DHAS:C ratio of 233:1 for ACTH and 7051:1 for “A.” However, this was not found in the more mature 915 mg gland (311:1 for ACTH and 191:1 for “A”). “B” reacted like ACTH. We conclude that (a) the developing fetal adrenal shows changing responses to different stimuli, perhaps reflecting changes in receptor response, number or discrimination, and (b) pituitary extract “A” may contain an androgen stimulator effective at variable stages of development.

Depression of atrioventricular sensitivity in the dog by successive brief bursts of vagal stimulation.

When identical, successive single vagal stimulations, separated in time (T) by 2-60 seconds, are applied in the dog, the peak change in atrioventricular conduction time for the second stimulus, deltaAV2, is less than that of the first, deltaAV1, that is, the ratio deltaAV2/deltaAV1 less than 1.0 (the mean minimum deltaAV2/deltaAV1=0.52). It was further determined that at any one given T, the actual value of deltaAV2/deltaAV1 also was a function of the first stimulus amplitude. The same dependence of deltaAV2/deltaAV1 on the first stimulus amplitude was found when the amplitude was varied either by (1) changing the number of vagal fibers stimulated for both the first and second response, but at a constant AD (the delay in the cardiac cycle at which the stimulus was given), or (2) by stimulating the same number of fibers but changing AD for both the first and second response. Also the same characteristic of deltaAV2/deltaAV1 plotted vs. T was found either (1) when both the first and second responses were produced by stimulation of the same nerve, or (2) when stimulated of the nerve from one side produced the first response and the alternate side the second response. These data suggest that the reason for this deltaAV2/deltaAV1 time-dependent effect lies in changes in receptor responsiveness or in acetylcholine inactivation, but not in mechanisms purely internal to the nerve terminal associated with synthesis, storage, or release of acetylcholine.