Opioid receptor-coupled second messenger systems

Although pharmacological data provide strong evidence for different types of opioid receptors (e.g., mu, delta, and kappa), they share many common properties in their ability to couple to second messenger systems. All opioid receptor types are coupled to G-proteins, since agonist binding is diminished by guanine nucleotides and agonist-stimulated GTPase activity has been identified in several preparations. Moreover, all three types inhibit adenylyl cyclase. This second messenger system has been identified for opioid receptors in both isolated brain membranes and in transformed cell culture. Studies with chronic treatment with opioid agonists suggest that the coupling of receptors with G-proteins and second messenger effectors may play important roles in development of opioid tolerance.     

Direct activation of second messenger pathways mimics cell adhesion molecule-dependent neurite outgrowth

We present evidence that direct activation of neuronal second messenger pathways in PC12 cells by opening voltage-dependent calcium channels mimics cell adhesion molecule (CAM)-induced differentiation of these cells. PC12 cells were cultured on monolayers of control 3T3 cells or 3T3 cells expressing transfected N-cadherin in the presence of KCl or a calcium channel agonist Bay K 8644. Both potassium depolarization and agonist-induced activation of calcium channels promoted substantial neurite outgrowth from PC12 cells cultured on control 3T3 monolayers and increased neurite outgrowth from those cultured on N-cadherin-expressing 3T3 monolayers. The potassium-induced response could be inhibited by L- and N-type calcium channel antagonists and by kinase inhibitor K-252b but was unaffected by pertussis toxin. In contrast activators of protein kinase C did not stimulate neurite outgrowth, and the neurite outgrowth response induced by activation of protein kinase A was not inhibited by calcium channel antagonists or pertussis toxin. These studies support the postulate that CAM-induced neuronal differentiation involves a specific transmembrane signaling pathway and suggest that activation of this pathway after CAM binding may be more important for the neurite outgrowth response than CAM-dependent adhesion per se.     

Calcium-dependent cell adhesion molecules

The adhesive function of Ca2(+)-dependent CAMS has in the past been studied only indirectly, mainly using immunological techniques. The molecular cloning and information about the primary structure of several CAMs has been an important step in a more detailed molecular analysis. If there is a homophilic interaction between CAMs of neighbouring cells, an important question concerns the specificity of each CAM-mediated adhesiveness. Has each CAM a unique specificity and can this specificity be linked to a defined amino acid sequence? It will be important to elucidate the molecular mechanism of how each CAM interacts with the other. The experiments of Volk et al. (1987) suggest that an interaction of two different CAMs can occur. Since during development a given cell can express more than one CAM such an heterophilic interaction could play some regulatory role. Alternative splicing mechanisms or different protein forms during development or on different cell types have not yet been observed for Ca2(+)-dependent CAMs. However, uvomorulin is assumed to have a slightly different function during development and in adult tissues. During development uvomorulin is involved in the condensation, the pattern formation, and the sorting out of cells. In these processes the uvomorulin-mediated adhesiveness should be controlled, since cells reorganize and migrate during development. For the maintenance of the histoarchitecture in adult tissues uvomorulin might act more as a glue. This argues for the existence of mechanisms to regulate the strength of adhesiveness, and the cytoplasmic domain might be involved in these processes. The association of the cytoplasmic domain of uvomorulin with catenins could be an important observation in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epithelial cell adhesion molecules

Recognition and binding between cells are of fundamental importance for a proper function of multicellular organisms, both during embryonic development and in the adult stage. Recently several cell surface proteins that are involved in these phenomena have been discovered. In the identification of these proteins, called cell adhesion molecules (CAMs), immunological methods have played a significant role. In a different approach to studies of cell-cell binding at the molecular level, the chemical composition of intercellular junctions is being studied. Intercellular junctions are specialized cell surface domains that have been identified by electron microscopy. They are particularly well developed in epithelia. Several proteins in the junctions have now been identified and characterized. This review deals with the biochemical properties of epithelial CAMs, and those proteins that are candidates for cell-to-cell binding in the junctions. In particular, the relationships between the various CAMs and junctional proteins are discussed. The tentative biological functions of these molecules are also considered.     

T cell adhesion molecules

Cell adhesion or conjugate formation between T lymphocytes and other cells is an important early step in the generation of the immune response. Although the antigen-specific T cell receptor confers antigen recognition and specificity, a number of other molecules expressed on the T cell surface are involved in the regulation of lymphocyte adhesion. T cell molecules that function to strengthen adhesion include lymphocyte function-associated antigen (LFA)-1, CD2, CD4, and CD8. Their ligands have recently been identified. LFA-1 is a member of the integrin family of adhesion receptors and one of its ligands is intercellular adhesion molecule-1 (ICAM-1); a ligand for CD2 is LFA-3; and ligands for CD4 and CD8 appear to be major histocompatibility complex class II and class I molecules, respectively. In addition, T cells express a number of receptors thought to be involved in cell matrix adhesion. The function and significance of these T cell adhesion receptors and their ligands are reviewed.     

神经细胞粘附分子

神经细胞粘附分子（ＮＣＡＭ）是一种糖蛋白,能介导细胞与细胞及细胞与细胞外基质间相互作用,它在细胞的识别及转移、肿瘤的浸润与生长、神经再生、跨膜信号的传导、学习和记忆等方面均起着一定的作用,本文对神经细胞粘附分子的结构、表达和功能加以概述,以增加对其的了解。     

Cell adhesion molecules: detection with univalent second antibody

Identification of cell surface molecules that play a role in cell-cell adhesion (here called cell adhesion molecules) has been achieved by demonstrating the inhibitory effect of univalent antibodies that bind these molecules in an in vitro assay of cell-cell adhesion. A more convenient reagent, intact (divalent) antibody, has been avoided because it might agglutinate the cells rather than blocking cell-cell adhesion. In this report, we show that intact rabbit immunoglobulin directed against certain cell surface molecules of Dictyostelium discoideum blocks cell-cell adhesion when the in vitro assay is performed in the presence of univalent goat anti-rabbit antibody. Under appropriate experimental conditions, the univalent second antibody blocks agglutination induced by the rabbit antibody without significantly interfering with its effect on cell-cell adhesion. This method promises to be useful for screening monoclonal antibodies raised against potential cell adhesion molecules because: (a) it allows for the screening of large numbers of antibody samples without preparation of univalent fragments; and (b) it requires much less antibody because of the greater affinity of divalent antibodies for antigens.     

Integrins and other cell adhesion molecules

Cell-cell and cell-substratum interactions are mediated through several different families of receptors. In addition to targeting cell adhesion to specific extracellular matrix proteins and ligands on adjacent cells, these receptors influence many diverse processes including cellular growth, differentiation, junction formation, and polarity. Several families of adhesion receptors have been identified. These include: 1) the integrins, heterodimeric molecules that function both as cell-substratum and cell-cell adhesion receptors; 2) the adhesion molecules of the immunoglobulin superfamily, which are involved in cell-cell adhesion and especially important during embryo-genesis, wound healing, and the inflammatory response; 3) the cadherins, developmentally regulated, calcium-dependent homophilic cell-cell adhesion proteins; 4) the LEC-CAMs, cell adhesion molecules with lectin-like domains that mediate white blood cell/endothelial cell adhesion; and 5) homing receptors that target lymphocytes to specific lymphoid tissue. In this review we summarize recent data describing the structure and function of some of these cell adhesion molecules (with special emphasis on the integrin family) and discuss the possible role of these molecules in development, inflammation, wound healing, coagulation, and tumor metastasis.     

Cell adhesion molecules, second messengers and axonal growth.

Recent studies on NCAM-related molecules suggest that individual cell adhesion molecules might function to both promote axonal growth during development and maintain synaptic structure in the adult. Evidence that differential alternative splicing contributes to this apparent bifunctionality of cell adhesion molecules is discussed.     

Neural cell adhesion molecules modulate tyrosine phosphorylation of tubulin in nerve growth cone membranes.

Triggering neural cell adhesion molecules of the immunoglobulin superfamily with specific ligands or antibodies inhibited the phosphorylation of tryosyl residues in a subpopulation of alpha- and beta-tubulin associated with membranes from a subcellular fraction of nerve growth cones from fetal rat brain. Preincubation of these membranes with purified extracellular fragments of L1, N-CAM, or myelin-associated glycoprotein, or with antibodies directed against the extracellular domains of L1 or N-CAM, inhibited pp60c-src-dependent phosphorylation of tubulin in an endogenous membrane kinase reaction. Other proteins that affect neurite outgrowth (fibronectin, laminin, antibodies against N-cadherin) had no effect. The results suggest that cell adhesion molecules transduce cell surface events to intracellular signals by modulating the activity of protein tyrosine kinases or phosphatases in axonal membranes to influence cytoskeletal dynamics at the growth cone.     

Heat shock effects on second messenger systems of Neurospora crassa

Exposure of growing hyphae of Neurospora crassa to heat shock (44 °C) or ethanol (2.6 M) for 1 h induced a significant increase in the cAMP level, which reached a maximum approximately 2 min after the beginning of treatment and then decreased to control values despite continued heat or ethanol exposure. A 10-s heat shock or a 5-s ethanol shock also resulted in a transient cAMP increase 2 min after the pulse. Heat shock or ethanol treatment led to an increase in the amount of catalytic subunits of the cAMP-dependent protein kinase A in the nucleus almost synchronously with the increase of cAMP in the cytoplasm. The concentration of cGMP decreased a few seconds after the beginning of heat shock (44 °C) or ethanol treatment (2.6 M) to approximately 50% of the control level. Exposure to heat shock (44 °C, 1 h) led to an increase in the amount of inositol phosphates 0.5–2 min after the onset of heat shock. Thereafter, inositol phosphate levels dropped to control values despite continued heat exposure. Incubation of growing hyphae with cAMP or 8-Br-cAMP led to a two- to threefold increase of inositol phosphates 10–300 s after the beginning of incubation. Heat treatment furthermore caused a rapid release of calcium from vacuoles as determined by Fura-2 measurement of the calcium content released from isolated vacuoles. These heat-shock-dependent second messenger changes may play a role in the heat-shock-induced phase shifts of the circadian clock and heat-shock-induced conidiation. Received: 7 July 1997 / Accepted: 2 June 1998     

On the adhesion of vesicles by cell adhesion molecules.

This paper gives a detailed analysis of experiments on the kinetics of aggregation of lipid vesicles containing neural cell adhesion molecules (N-CAM). An explanation for the dependence of the "initial aggregation rate," kagg, on the square of the vesicle concentration is given, accounting both for Brownian motion of the vesicles and shear effects. A model in which trimers of N-CAM are one-half of the molecular unit bridging two vesicles explains the observed dependence of kagg on up to the sixth power of the lateral N-CAM concentration and corroborates electron micrographic evidence for N-CAM "triskelions."     

Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion

Binding interactions between the plasma membrane and the cytoskeleton define cell functions such as cell shape, formation of cell processes, cell movement, and endocytosis. Here we use optical tweezers tether force measurements and show that plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a second messenger that regulates the adhesion energy between the cytoskeleton and the plasma membrane. Receptor stimuli that hydrolyze PIP2 lowered adhesion energy, a process that could be mimicked by expressing PH domains that sequester PIP2 or by targeting a 5'-PIP2-phosphatase to the plasma membrane to selectively lower plasma membrane PIP2 concentration. Our study suggests that plasma membrane PIP2 controls dynamic membrane functions and cell shape by locally increasing and decreasing the adhesion between the actin-based cortical cytoskeleton and the plasma membrane.     

Functional domains of cell adhesion molecules.

A number of molecules involved in cell adhesion (e.g. fibronectin, laminin, collagens I and IV, thrombospondin, entactin) have now been identified and the consequent roles that they play in the processes of growth, migration, differentiation and tumor spread have been described. Active sequences of the molecules have been identified using synthetic peptides derived from specific domains. Several adhesive molecules contain multiple active domains with different biological activities.     

Neural circuit formation in the cerebellum is controlled by cell adhesion molecules of the Contactin family

Cell adhesion molecules of the -immunoglobulin superfamily (IgSF CAMs) have been implicated in neural circuit formation in both the peripheral and the central nervous system. Several recent studies highlight a role of the Contactin group of IgSF CAMs in cerebellar development, in particular in the development of granule cells. Granule cells are the most numerous type of neurons in the nervous system and by forming a secondary proliferative zone in the cerebellum they provide an exception to the rule that neuronal precursors proliferate in the ventricular zone. Granule cells express Contactin-2, Contactin-1 and Contactin-6 in a sequential manner. Contactins are required for axon guidance, fasciculation and synaptogenesis, and thus affect multiple steps in neural circuit formation in the developing cerebellum.Key words: immunoglobulin superfamily cell adhesion molecule, parallel fibers, granule cells, axon guidance, synaptogenesis     

Neural circuit formation in the cerebellum is controlled by cell adhesion molecules of the Contactin family

Cell adhesion molecules of the immunoglobulin superfamily (IgSF CAMs) have been implicated in neural circuit formation in both the peripheral and the central nervous system. Several recent studies highlight a role of the Contactin group of IgSF CAMs in cerebellar development, in particular in the development of granule cells. Granule cells are the most numerous type of neurons in the nervous system and by forming a secondary proliferative zone in the cerebellum they provide an exception to the rule that neuronal precursors proliferate in the ventricular zone. Granule cells express Contactin-2, Contactin-1, and Contactin-6 in a sequential manner. Contactins are required for axon guidance, fasciculation, and synaptogenesis, and thus affect multiple steps in neural circuit formation in the developing cerebellum.