Signalling mechanisms

A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Neurobiology.     

Signalling mechanisms of anoikis

Apoptosis following loss of cell anchorage ('anoikis') is of relevance for development, tissue homeostasis and disease. Integrins regulate cell viability through their interaction with the extracellular matrix and they can sense mechanical forces arising from the matrix and convert these stimuli to chemical signals capable of modulating intracellular signal transduction. Recently it has been shown that protein kinase signalling pathways and apoptosis-related molecular control anoikis both positively and negatively. Focal adhesion kinase, when activated by integrins, can suppress anoikis. Phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase may mediate the anoikis-suppressing effects of cells. Conversely, the stress-activated protein kinase/Jun amino-terminal kinase pathway promotes anoikis. In addition, certain bcl-2 and bcl-2-related proteins may also participate in the regulating of anoikis. In this review, molecular mechanisms of signal pathway inducing and perpetuating detachment-induced apoptosis will be discussed with special emphasis on the role of integrins, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase and bcl-2 family members.     

Signalling mechanisms regulating lipolysis

Adipose tissue plays an important role providing energy to other tissues and functioning as an energy reserve organ. The energy supply is produced by triglycerides stored in a large vacuole representing approximately 95% of adipocyte volume. In the fasting period, triglyceride hydrolysis produces glycerol and free fatty acids which are important oxidative fuels for other tissues such as liver, skeletal muscle, kidney and myocardium. Hormone-sensitive lipase (HSL) is the enzyme that hydrolyzes intracellular triacylglycerol and diacylglycerol, and is one of the key molecules controlling lipolysis. Hormones and physiological factors such as dieting, physical exercise and ageing regulate intensively the release of glycerol and free fatty acids from adipocytes. One of the best known mechanisms that activate lipolysis in the adipocyte is the cAMP dependent pathway. cAMP production is modulated by hormone receptors coupled to Gs/Gi family of GTP binding proteins, such as beta-adrenergic receptors, whereas cAMP degradation is controlled by modulation of phosphodiesterase activity, increased by insulin receptor signalling. cAMP activates PKA which activates HSL by promoting its phosphorylation. Hormonal control of lipolysis can also be achieved by receptors coupled G proteins of the Gq family, through molecular mechanisms that involve PKC and MAPK, which are currently under investigation. cGMP and PKG have also been found to activate lipolysis in adipocytes. In this review we have compiled data from literature reporting both the classical and the alternative mechanisms of lipolysis.     

蛋白激酶C与缺血预处理心肌保护作用

蛋白激酶Ｃ（ＰＫＣ）是心肌细胞磷脂酰肌醇信号转导系统的重要组成部分,ＰＫＣ在缺血预处理（ＩＰ）过程中的移位和激活在ＩＰ的心肌保护中发挥了关键的作用。ＰＫＣ介导ＩＰ心肌保护作用的机制与其磷酸化底物蛋白有关,包括激活细胞外－５‘－核苷酸酶,激活ＡＴＰ敏感性钾通道以及维持细胞内Ｃａ＾２＋稳态。对ＰＫＣ发挥ＩＰ心肌保护作用机制的探索将为人类心血管疾病的治疗提供新的理论基础和药理手段。     

Signalling mechanisms: Web alert

A selection of World Wide Web sites relevant to the reviews published in this issue of Current Opinion in Neurobiology.     

Signalling mechanisms: a decade of signalling

Knowledge of signaling mechanisms has increased dramatically during the past decade, particularly in the areas of development, biochemical signaling cascades, synaptic transmission and ion channel biophysics.     

低氧预适应的脑机制

A concept ot tissue adaptation to hypoxia( i.e. hypoxic preconditioning) was developed and its corresponding animal models were reproduced in 1966s. The methods of model reproduction in rat, rabbit, and mouse in particular and the main results are brifly introduced in this review. The tolerance to hypoxia o{ preconditioned animals is significantly increased. Regular changes in animals‘ behavior, neurophysiology, respiratory and circulatory physiology, neuromorphology in vivo and {unction of brain and spinal cord in vitro are briefly demonstrated. The protective effects in vivo and in vitro of homogenate extract taken from the brain o{ preconditioned animals, neurochemcals and molecular neurobiolcgical alterations are briefly presented. The essence and significance of tissue adaption to hypoxia/hypoxic preconditioning are discussed in the review in terms of evolution and practical implication.     

Dopamine mimics the cardioprotective effect of ischemic preconditioning via activation of alpha1-adrenoceptors in the isolated rat heart

The aim of the present study was to clarify whether pharmacological preconditioning with dopamine protects the heart against ischemia and whether this effect is mediated through dopaminergic receptors (D1 and D2) or alpha1-adrenoceptors. Isolated perfused rat hearts were either non-preconditioned, preconditioned with 5 min ischemia, or treated for 5 min with dopamine (1, 5 or 10 microM) before being subjected to 45 min of sustained ischemia followed by 60 min reperfusion. Postischemic functional recovery and infarct size were used as indices of the effects of ischemia. Treatment with the lower concentration of dopamine (1 microM), did not provide any protection to the ischemic myocardium. On the other hand, treatment with 5 microM dopamine resulted in significantly improved functional recovery, whereas administration of dopamine (10 microM) resulted in significantly improved functional recovery as well as reduction of infarct size. Pretreatment with the mixed D1/D2 dopaminergic receptor antagonist haloperidol or the beta-adrenoceptor selective antagonist propranolol did not attenuate the protective effect of pharmacological preconditioning with 10 microM dopamine with respect to both functional recovery and infarct size reduction. On the other hand, the cardioprotective effect of dopamine was blocked when the alpha1-adrenoceptor selective antagonist, prazosin, was administered. In conclusion, pharmacological preconditioning with dopamine protects the myocardium against ischemia and this effect seems to be mediated through activation of alpha1-adrenoceptors.     

Role of receptor transactivation in the cardioprotective effects of preconditioning and postconditioning

Analysis of published data indicates that the activity of receptors for adenosine, opioids, bradykinin, calcitonin-gene related peptides (CGRP) and epidermal growth factor (EGF) play important role in triggering the cardioprotective effects of ischemic preconditioning. Cannabinoids mimic the infarct-sparing effects of preconditioning. Endogenous adenosine, opioids, bradykinin and CGRP have also been implicated in infarct-reduction with ischemic postconditioning. Again, cannabinoids also mimic the protective effect of postconditioning. Recent works support heterodimerization of G-protein coupled receptors (GPCRs), and GPCR transactivation of EGF receptors. It was found that cross-talk between delta(j)-opioid receptors and adenosine A(1)-receptors is essential to cardiac protection. Furthermore, evidence implicates EGF receptor transactivation in cardioprotective effect of multiple GPCrs including adenosine, acetylcholine, bradykinin, and opioid receptors. Such findings support a convergent pathway in which multiple GPCRs may interact (or function independently) to transactivate EGF receptor-dependent kinase signaling and cytoprotection.     

Signalling mechanisms mediating neuronal responses to guidance cues

Several families of extracellular guidance cues have been implicated in guiding neurons and axons to their appropriate destinations in the nervous system. Their receptors include single- and seven-transmembrane receptors, and their signal transduction pathways converge onto the Rho family of small GTPases, which control the cytoskeleton. A single guidance protein can use different mechanisms to regulate different kinds of motility or the motilities of different cell types. There is crosstalk between the signalling pathways initiated by distinct guidance cues. Studies of neuronal guidance mechanisms have shed light not only on neural development, but also on other processes that involve the extracellular regulation of the cytoskeleton.