Intracellular Signal Transmission Research Articles

Role of cardiovascular phospholipase A2 and C in the development of DOCA-salt hypertensive rats.

There is much evidence that phospholipids metabolism is related to intracellular signal transmission system (1,2,3). Besides adenosine 3′:5′-cyclic monophosphate (cyclic AMP) and protein kinase A system, phosphoinositides metabolism has recently been emphasized as an intracellular calcium messenger system which modulates cytosolic free calcium concentration, and mediates the subsequent transmission of signals (3).Phospholipase C, which is activated by receptor mediated mechanisms, has been found to initiate the intracellular transmission of signals. Furthermore, in concerting with diacylglycerol lipase, phospholipase C provides arachidonate for prostaglandin (PG) generation (4,5). In conjunction with this, phospholipase A2is also known to directly hydrolyze sn-2-position of phospholipids, increasing free arachidonate pool available for PG synthesis. Thus, it is conceivable that phospholipases in cardiovascular system influence the regulatory mechanism for hemodynamics and body fluid homeostasis through their intracellular actions.

Activation of inositol phosphate formation by circulating noradrenaline but not by sympathetic nerve stimulation with a similar increase of glucose release in perfused rat liver.

In the isolated rat liver perfused in situ, stimulation of the nerve bundles around the hepatic artery and portal vein caused an increase of glucose and lactate output and a reduction of perfusion flow. These changes could be inhibited completely by alpha-receptor blockers. The possible involvement of inositol phosphates in the intracellular signal transmission was studied. 1. In cell-suspension experiments, which were performed as a positive control, noradrenaline caused an increase in glucose output and, in the presence of 10 mM LiCl, a dose-dependent and time-dependent increase of inositol mono, bis and trisphosphate. 2. In the perfused rat liver 1 microM noradrenaline caused an increase of glucose and lactate output and in the presence of 10 mM LiCl a time-dependent increase of inositol mono, bis and trisphosphate that was comparable to that observed in cell suspensions. 3. In the perfused rat liver stimulation of the nerve bundles around the portal vein and hepatic artery caused a similar increase in glucose and lactate output to that produced by noradrenaline, but in the presence of 10 mM LiCl there was a smaller increase of inositol monophosphate and no increase of inositol bis and trisphosphate. These findings are in line with the proposal that circulating noradrenaline reaches every hepatocyte, causing a clear overall increase of inositol phosphate formation and thus calcium release from the endoplasmic reticulum, while the hepatic nerves reach only a few cells causing there a small local change of inositol phosphate metabolism and thence a propagation of the signal via gap junctions.

Influence of cyclooxygenase inhibitors and of lithium on the positive inotropic effect mediated by alpha 1-adrenoceptors in guinea-pig left atrium.

In experiments on the isolated guinea-pig left atrium we tried to get more information about the intracellular signal transmission of the alpha 1-adrenoceptor. We were able to demonstrate that the cyclooxygenase inhibitors indometacin and acetylsalicylic acid enhance the positive inotropic effect of relatively low phenylephrine concentrations at an extracellular calcium concentration of 1.22 mmol/l. Preincubation with prazosin as well as an increased calcium concentration of 2.5 mmol/l abolished this effect. These observations led us to suppose that an elevated level of receptor-generated arachidonic acid, whose degradation is inhibited by the cyclooxygenase inhibitors, caused the increased contractility by releasing more calcium from the sarcoplasmic reticulum. Under these conditions also lithium caused a distinct enhancement of the positive inotropic effect evoked by alpha 1-adrenergic agonists, probably by inhibiting the degradation of the second messenger inositol trisphosphate.

Physiological roles of permeable junctions: some possibilities.

It has been nearly two decades since penneable intercellular junctions were first detected between electrically nonexcitable cells (27, 33). Considerable prog­ ress has been made in our understanding of the structure, permeability, dis­ tribution, and biochemistry of the junctions (see 9, 24, 54, 71 in this volume). Much less progress has been made, however, in our understanding of the biological roles played by the junctions, despite the common use of the term communication. In fact most of the original functional specula­ tions, e.g. involvement in exchange of nutrients (27), maintenance of tissue homeostasis (73), regulation of cell growth and differentiation (25, 50), and transmission of intracellular molecular signals (61), are still frequently cited in the literature with rather little in the way of experimental support. A major problem in trying to design experiments to test these various ideas has been the lack of a specific and reversible method for interrupting junctional permeabil­ ity. Consequently, it has been necessary to rely on more indirect approaches, for example correlating patterns of junctional distribution and changes in junctional permeability with specific physiological and pathological events. In this review we discuss a few of the recently studied systems in which these indirect approaches have been quite useful. Rather than be exhaustive, we have selected cell systems that reflect general concepts regarding junctional com­ munication, that illustrate the range of strategies currently available to study the physiology and pathology of the junctions, and that have particular promise for

Elongation of cytoplasmic processes during gametic mating: models for actin-based motility.

The acrosomal processes of Thyone and Limulus sperm and the fertilization tubule of mt+ gametes of Chlamydomonas are interesting models for actin-based motility. Each is a long thin process that elongates rapidly and contains a core of actin filaments having uniform polarity: arrowheads formed by myosin subfragments point toward the base of the processes. In Limulus, directed outgrowth of the acrosomal process is achieved by a rearrangement in the packing of superhelically coiled actin filaments that form during spermatogenesis. In contrast, outgrowth of the acrosomal process in Thyone and the fertilization tubule in Chlamydomonas is accompanied by actin polymerization. Both Thyone and Chlamydomonas possess structures, the actomere and the doublet zone, respectively, that serve as microfilament organizing centers, nucleating actin polymerization and defining the polarity of the growing filaments. Alkalinization of the cytoplasm may promote polymerization of actin in Thyone, whereas an apparent rise in the intracellular Ca2+ concentration is associated with the transmission of intracellular signals during mating in Chlamydomonas. Further examination of these three actin-based motile systems should provide new insights into the assembly of the actin cytoskeleton, a process critical for many forms of nonmuscle cellular motility.