Autocrine receptor

Transport in the blood is no longer a requisite for a hormonal response. Responses can occur after release of hormones into the interstitial fluid with binding to receptors in nearby ceUs, called paracrine control, or binding to receptors on the ceU that released the hormone, called autocrine control. A class of hormones shown to be synthesized by the tissue in which they act or to act in the local ceUular environment are the prostaglandins (qv). These ubiquitous compounds are derived from arachidonic acid [506-32-1] which is stored in the ceU membranes as part of phosphoHpids. Prostaglandins bind to specific ceUular receptors and act as important modulators of ceU activity in many tissues. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Somatostatin acts on various organs, tissues and cells as neurotransmitter, paracrine/autocrine and endocrine regulator on cell secretion, smooth muscle contractility, nutrient absorption, cell growth and neurotransmission [1]. Some of its mainly inhibitory effects are listed in Table 1. Somatostatin mediates its function via a family of heptahelical G-protein-coupled receptors termed... 

It is of interest that proteins termed motility factors (55-70 kD) are secreted by fetal cells and some tumor cells. These proteins act as autocrine factors and stimulate rapid movement by these cells. Motility factors induce the formation of cell processes that are packed with actin filaments and have an increased number of receptors for the matrix proteins laminin and fibronectin. The latter enhance the ability of the cells to bind to the extracellular matrix. Thus, it is likely that motility factors influence the organization of the cytoskeleton through changes taking place at the cell surface (reviewed by Warn and Dowrick, 1989). 

Figure 1. Autocrine and paracrine factors. Many animal cells secrete regulatory factors called autocrine factors, which then interact with specific receptors on the surface of the same cells, so as to modulate cell function. Animal cells may also secrete regulatory factors called paracrine factors, which interact with specific receptors on different cells in the same locale, modulating their functional properties.

Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res 2002 62(24) 7203-7206. 

Nearly all of the interleukins are soluble molecules (one form of IL-1 is cell associated). They promote their biological response by binding to specific receptors on the surface of target cells. Most interleukins exhibit paracrine activity (i.e. the target cells are in the immediate vicinity of the producer cells), although some display autocrine activity (e.g. IL-2 can stimulate the growth and differentiation of the cells that produce it). Other interleukins display more systematic endocrine effects (e.g. some activities of IL-1). 

Table 9.3 The range of cells expressing the IL-2 cell surface receptor. IL-2-stimulated growth and differentiation of these cells forms the molecular basis by which many aspects of the immune response are activated. It thus acts in an autocrine and paracrine manner to mobilize...

Table 10.1 Overview of some polypeptide growth factors. Many can be grouped into families on the basis of amino acid sequence homology, or the cell types affected. Most growth factors are produced by more than one cell type and display endocrine, paracrine or autocrine effects on target cells by interacting with specific cell surface receptors...

The liver represents the major site of synthesis of the IGFs, from where they enter the blood stream, thereby acting in a classical endocrine fashion. A wide variety of body cells express IGF receptors, of which there are two types. Furthermore, IGFs are also synthesized in smaller quantities at numerous sites in the body and function in an autocrine or paracrine manner at these specific locations. IGF activity is also modulated by a family of IGFBPs, of which there are at least six. 

Purines such as ATP and adenosine play a central role in the energy metabolism of all life forms. This fact probably delayed recognition of other roles for purines as autocrine and paracrine substances and neurotransmitters. Today it is recognized that purines are released from neurons and other cells and that they produce widespread effects on multiple organ systems by binding to purinergic receptors located on the cell surface. The principal ligands for... 

NGF also has actions within the CNS, although it is not particularly abundant in the CNS. Its synthesis appears to be largely restricted to the hippocampus and neocortex, and even in these regions it is present at relatively low concentrations relative to the other neurotrophins. The most prominent population of NGF-responsive neurons expressing TrkA are the basal forebrain cholinergic neurons. The principal projections of these neurons are to the hippocampus and cortex, which conforms with the concept that NGF acts as a target-derived trophic factor in the CNS, just as it does in the peripheral nervous system (PNS). NGF also acts on a subpopulation of cholinergic neurons within the striatum. These interneurons express the NGF receptor, TrkA, and respond to NGF. However, they do not appear to rely entirely on NGF for their survival, and the specific actions of NGF on this neuronal population have not been clearly defined. NGF may also have autocrine actions in the CNS, as some neuronal populations have been identified that express both TrkA and NGF. 

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

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