It seems that CaMKII phosphorylation

of PhLP1 stabilizes the PhLP1.G beta gamma complex by promoting its binding to 14-3-3 proteins. When this complex fails to bind to 14-3-3 proteins, the association of PhLP1 with G beta gamma is probably disrupted by G alpha GDP subunits and the MORs recover control on G proteins. (C) 2007 Elsevier Ltd. All rights reserved.”
“Glucocorticoid (GC)-induced apoptosis is essential in the treatment of acute lymphoblastic leukemia (ALL) and related malignancies. Pro-and anti-apoptotic members of the BCL2 family control many forms of apoptotic cell death, but the extent to which this survival ‘rheostat’ is involved in the beneficial effects of GC 1 therapy is not understood. We performed systematic analyses of expression, GC regulation and function of BCL2 molecules in primary ALL lymphoblasts and a corresponding in vitro model. Affymetrix-based expression profiling revealed that the response included regulations of pro-apoptotic and, surprisingly, anti-apoptotic BCL2 family members, and varied among patients, but was dominated by induction of the BH3-only molecules BMF and BCL2L11/Bim and repression

of PMAIP1/Noxa. Conditional lentiviral gene overexpression and knock-down by RNA interference in the CCRF-CEM model revealed that induction of Bim, and to a lesser extent that of BMF, was required and sufficient for apoptosis. Although anti-apoptotic BCL2 members were not regulated consistently by GC in the various systems, their overexpression delayed, whereas their knock-down accelerated, GC-induced cell death. Thus, the combined clinical and experimental data

suggest that GCs induce both pro-and antiapoptotic BCL2 family member-dependent pathways, with the outcome depending on cellular context and additional signals feeding into the BCL2 rheostat.”
“Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at g-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki = 0.034 mu M) for mu-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC50 = 4.2, 3.3 and 3.5 mu M in cortex, hippocampus and striatum respectively). NS7051 (1-30 mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED50 = 1.7 and 1.8 mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund’s adjuvant injection (ED50 = 1.2 mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50 = 6.