chapter 8 general modes of intercellular signaling

© 2020 Elsevier Inc. All rights reserved.

Chapter 8General Modes of Intercellular

Signaling

© 2020 Elsevier Inc. All rights reserved. 2

Figure 8–1. Intercellular signaling molecules are ligands and exert their effects via interaction with specific target cell receptors.

Signaling molecules that are large and hydrophilic cannot enter the target cell by diffusion and exert their effects via interaction with cell

surface receptors (A). These receptors can be ion channels, G-protein coupled, or enzyme coupled. Receptor-mediated changes in

downstream second messenger pathways alter cell behavior. Small/hydrophobic signaling molecules readily diffuse into the target cell

and interact with receptors located inside the cell (B). These ligand-receptor complexes then bind to regulatory regions in DNA and

promote the transcription of new gene products that alter cell behavior.


Figure 8–2. Signaling molecules are versatile and induce differential responses. In the salivary gland (A), acetylcholine activates a

muscarinic receptor subtype, resulting in secretion. In the heart muscle (B), acetylcholine activation of the same muscarinic receptor

subtype has a different biological effect, decreased rate, and force of contraction. The differential effects on cell behavior are due to the

coupling of the muscarinic receptor to different intracellular signaling pathways in the two cell types. In skeletal muscle (C), acetylcholine

activates a different receptor subtype, the nicotinic receptor, resulting in depolarization of the muscle cell and contraction.


Figure 8–3. General schemes of intercellular signaling. Cell-to-cell signaling can occur over short (A–C) or long distances (D, E). In

paracrine signaling (A), chemicals are released into the extracellular environment and exert their effects on neighboring target cells that

express the appropriate receptor. In autocrine signaling (B), the cell that synthesizes/releases the signaling molecule is also the target

cell. In juxtacrine signaling (C), the signaling molecule remains attached to the plasma membrane and interacts with receptors on

adjacent target cells. In endocrine signaling (D), hormones are released into the circulation and distribute throughout the body but alter

only the behavior of cells that express the appropriate receptor. Synaptic signaling (E) is a specialized form of paracrine signaling that

occurs over long distances because the signal is transmitted along neuronal cell processes that can span the entire length of the

organism. Specificity in synaptic signaling is generated by the formation of synaptic contacts and not the signaling

molecule/neurotransmitter.


Figure 8–4. Gene regulation by members of the nuclear receptor superfamily. (A) The inactive glucocorticoid receptor is located in

the cytosol in a complex that contains heat shock protein (Hsp) 70, Hsp90, and immunophilin (IP). Cortisol binding to the receptor

displaces accessory proteins, and the activated ligand-receptor complex translocates to the nucleus where it activates target genes. (B)

The inactive estrogen receptor Hsp90 complex is located in the nucleus. Estrogen binding displaces Hsp90 and the activated receptors

dimerize, bind to DNA, associate with the coactivator histone acetyltransferase (HAT), and activate target genes. (C) The thyroid hormone

receptor binds DNA in the presence and absence of ligand. In the absence of ligand, the receptor is complexed with the corepressor

histone deacetylase (HDAC), which prevents gene transcription. In the presence of hormone, the ligand-receptor complex binds the

coactivator HAT and activates target gene expression.


Figure 8–5. Hypophysiotropic control of pituitary hormones. Neuronal cells in various nuclei/regions of the hypothalamus release

signaling molecules into the bloodstream, rather than synapses. These signaling molecules (blue) travel through the bloodstream to the

pituitary where they stimulate (solid lines) or inhibit (dashed lines) the release of one or more pituitary hormones (purple).


Figure 8–6. Regulation of GH release. GH release from the pituitary is stimulated by growth hormone–releasing hormone (GHRH),

which peaks at night, and inhibited by somatostatin, which reaches high levels during the day. GH then stimulates the growth of muscle

and adipocytes and the release of IGF-1 from the liver. IGF-1 then stimulates bone growth. If there are adequate metabolic fuels,

metabolic signals from the peripheral target tissues will act on the hypothalamus and stimulate GH release. GH and IGF-1 provide

negative feedback and inhibit the release of GHRH from the hypothalamus. IGF-1 also inhibits GH release from somatotropes in the

pituitary.


Figure 8–7. Extracellular matrix components modulate FGF activity. FGF interacts with the heparin sulfate side chains found on

proteoglycans in the extracellular matrix and bound to the plasma membrane. These proteoglycans act as low-affinity receptors for FGF,

sequester the FGF, and prevent its degradation. FGF interaction with HS is required for high-affinity interaction with its receptor FGFR.

The formation of an FGF/FGFR/heparan sulfate (HS) (2: 2: 2) dimer induces the transphosphorylation of the cytoplasmic receptor tyrosine

kinase domains that activates FGF signaling and alters cell behavior.


Figure 8–8. Mast cell degranulation/histamine signaling. Mast cells and eosinophils in the blood contain large numbers of secretory

granules that are filled with histamine. In the case of an allergic reaction, binding of the allergen to an IgE antibody immobilized on the

mast cell triggers the release of histamine-containing granules. The released histamine binds endothelial and smooth-muscle H1

receptors to induce vasodilation. If concentrations are high enough, the released histamine acts on eosinophil H4 receptors to induce their

migration into the affected area. These eosinophils can then exacerbate the reaction by releasing additional histamine.


Figure 8–9. NO-mediated endothelial cell relaxation. eNOS produces NO in endothelial cells in response to a variety of intercellular

signaling molecules including acetylcholine, histamine, bradykinin, and adenosine triphosphate (ATP). NO diffuses out of the endothelial

cell and into the vascular smooth-muscle cell, where it binds to the heme (iron) moiety in guanylate cyclase. This increases cGMP levels

and activates the cGMP-dependent kinases that ultimately produce smooth relaxation/vasodilation. During stress, iNOS will be activated,

and NO levels will increase.


Figure 8–10. Eicosanoid-mediated intercellular signaling. Arachidonic acid, liberated from phospholipase A hydrolysis of plasma

membrane phospholipids, is the precursor for all members of the eicosanoid family. The major signaling metabolites (blue), their

receptors (yellow), and biological responses (yellow) are listed.


Figure 8–11. Electrical and chemical synapses. In an electrical synapse (A), gap junctions allow current to flow directly from the

presynaptic cell to the postsynaptic cell. In a chemical synapse (B), the presynaptic cell converts the current into a chemical signal.

Neurotransmitters (yellow), located in synaptic vesicles, and larger neuropeptides, located in dense core granules, form the chemical

signal. The neurotransmitters are released into the synaptic cleft and interact with ligand-mediated G protein–coupled receptors or ligand-

mediated ion channel receptors on the postsynaptic cell. Neuropeptide (red) release occurs adjacent to the synaptic cleft. An action

potential will be generated in the postsynaptic cell only if these chemicals produce a sufficient depolarization.


Figure 8–12. Synaptic transmission at the neuromuscular junction. (A) The neuromuscular junction is composed of synaptic

boutons from the innervating α-motor neuron and the specialized motor end plates on the muscle fiber. Acetylcholine is synthesized in the

motor neuron terminal and taken up into synaptic vesicles (yellow). (B) On release the acetylcholine diffuses across the synaptic cleft and

binds to a ligand-gated ion channel (red). The number of Na+ molecules that enter the muscle cell is dependent on the number of

acetylcholine molecules released from the neuron. If there is a sufficient depolarization, then action potential will be generated in the

muscle cell, and contraction will occur. Acetylcholinesterase, located in the synaptic cleft, hydrolyzes acetylcholine to acetate and choline.

The choline is taken back up into the presynaptic cleft and used to refill synaptic vesicles.


Figure 8–13. Synaptic transmission in the central nervous system. Neurons in the CNS have many synaptic contacts distributed on

the cell body (Input A), dendritic tree (Inputs B and C), and terminal boutons (Input D). Some of these contacts are excitatory, resulting in

EPSPs (Inputs A and B), and others are inhibitory, resulting in IPSPs (Input C). The ultimate decision of whether to fire an AP is

determined by the weighted integral of all of these inputs over time.

chapter 8 general modes of intercellular signaling

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