Plasma protease inhibitors in mouse and man: divergence within the reactive centre regions

The plasma protease inhibitors control a wide variety of physiological functions including blood coagulation, complement activation and aspects of the inflammatory response. The inhibitors function by forming a 1:1 complex with a specific protease within the reactive centre region of the inhibitor. Little is known about the evolutionary relationships of these inhibitors. We report here the sequences of cDNAs which represent the C-terminal halves of the two major murine plasma protease inhibitors. One of these, murine alpha 1-antitrypsin, more appropriately called alpha 1-proteinase inhibitor (alpha 1-PI), has diverged from its human counterpart at a vital position in the reactive centre but this has not led to a physiologically significant change in function. Also, we have determined the partial sequence of a recently characterized protein termed contrapsin, which inhibits trypsin-like proteases. We show, surprisingly, that contrapsin is highly homologous to human alpha 1-antichymotrypsin, an inhibitor of chymotrypsin-like proteases. The reactive centre regions of these two inhibitors have diverged considerably, which may account for the differences in specificity. We propose that the genes for contrapsin and human alpha 1-antichymotrypsin are the descendents of a single gene that have evolved since rodent and primate divergence to encode proteins with different functions.     

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.     

Prostaglandins and the synergism between VIP and noradrenaline in the cerebral cortex

We have previously shown that vasoactive intestinal peptide (VIP) and noradrenaline (NA) interact synergistically to increase cyclic AMP levels in mouse cerebral cortical slices. The pharmacological mechanism of this synergism is the potentiation by NA, through alpha 1 adrenergic receptors, of the stimulatory effect of VIP on cAMP formation. A similar interaction has been confirmed in guinea pig cerebral cortex and in discrete nuclei of the rat hypothalamus. Furthermore VIP and NA interact synergistically to depress the spontaneous activity of identified neurons in rat neocortex. At the cellular level, this synergistic interaction suggests that VIP- and NA-containing neuronal systems may converge, at least in part, on the same target cells to increase cAMP levels in the cerebral cortex. At the molecular level, the interaction may occur at various steps in signal transduction, between receptors, intramembrane transduction processes or intracellular effector mechanisms. Here we report that the alpha 1-adrenergic potentiation of the increases in cAMP elicited by VIP involves the formation of arachidonic acid metabolites and is mimicked by prostglandins F2 alpha and E2.     

蛋白激酶C阳性细胞在大鼠大脑皮质和海马结构的分布

目的：观察蛋白激酶C(PKC)阳性细胞在大鼠大脑皮质和海马结构的形态和分布，为更好地研究PKC在中枢神经系统的生理作用提供形态学的基础。方法：用免疫组织化学方法检测了大脑皮质和海马结构PKC阳性细胞的分布。结果：PKC阳性细胞脑体较小，多呈卵圆形，少数呈三角形，多数突起较短。PKC阳性细胞主要分布在大脑的额叶、顶叶、颞叶和枕叶的Ⅱ、Ⅲ和Ⅳ层，在杏仁海马移行区和杏仁梨状皮质移行区也有分布。海马结构中主要分布在下托和齿状回的颗粒层、海马CAI区的锥体层和辐射层。结论：在大脑皮质和海马结构有PKC阳性细胞的广泛分布。