Which of the Following is Not a Category of Endocrine Gland Stimulus Easy Notecards

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As mentioned previously, hormones produce their biologic effects by binding to specific

hormone receptors in target cells, and the type of receptor to which they bind is largely determined by the hormone's chemical structure. Hormone receptors are classified depending on their cellular localization, as cell membrane or intracellular receptors. Peptides and catecholamines are unable to cross the cell membrane lipid bilayer and in general bind to cell membrane receptors, with the exception of thyroid hormones as mentioned above. Thyroid hormones are transported into the cell and bind to nuclear receptors. Steroid hormones are lipid soluble, cross the plasma membrane, and bind to intracellular receptors.

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Cell Membrane Receptors

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These receptor proteins are located within the phospholipid bilayer of the cell membrane of target cells (Figure 1–5). Binding of hormones (ie, catecholamines, peptide and protein hormones) to cell membrane receptors and formation of the hormone-receptor complex initiates a signaling cascade of intracellular events, resulting in a specific biologic response. Functionally, cell membrane receptors can be divided into ligand-gated ion channels and receptors that regulate activity of intracellular proteins.

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Figure 1–5.

Graphic Jump Location

G protein–coupled receptors. Peptide and protein hormones bind to cell surface receptors coupled to G proteins. Binding of the hormone to the receptor produces a conformational change that allows the receptor to interact with the G proteins. This results in the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) and activation of the G protein. The second-messenger systems that are activated vary depending on the specific receptor, the α-subunit of the G protein associated with the receptor, and the ligand it binds. Examples of hormones that bind to G protein–coupled receptors are thyroid hormone, arginine  vasopressin, parathyroid hormone, epinephrine, and glucagon. ACTH, adrenocorticotropic hormone; ADP, adenosine diphosphate; cAMP, cyclic 3′,5′-adenosine monophosphate; DAG, diacylglycerol; FSH, follicle-stimulating hormone; GHRH, growth hormone-releasing hormone; GnRh, gonadotropin-releasing hormone; IP3, inositol trisphosphate; LH, luteinizing hormone; PI3Kγ, phosphatidyl-3-kinase; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC-β, phospholipase C; RhoGEFs, Rho guanine-nucleotide exchange factors; SS, somatostatin; TSH, thyroid-stimulating hormone.

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Ligand-Gated Ion Channels

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These receptors are functionally coupled to ion channels. Hormone binding to this receptor produces a conformational change that opens ion channels on the cell membrane, producing ion fluxes in the target cell. The cellular effects occur within seconds of hormone binding.

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Receptors that Regulate Activity of Intracellular Proteins

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These receptors are transmembrane proteins that transmit signals to intracellular targets when activated. Ligand binding to the receptor on the cell surface and activation of the associated protein initiate a signaling cascade of events that activates intracellular proteins and enzymes and that can include effects on gene transcription and expression. The main types of cell membrane hormone receptors in this category are the G protein–coupled receptors and the receptor protein tyrosine kinases. An additional type of receptor, the receptor-linked kinase receptor, activates intracellular kinase activity following binding of the hormone to the plasma membrane receptor. This type of receptor is used in producing the physiologic effects of growth hormone (see Figure 1–5).

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G Protein–Coupled Receptors

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G protein–coupled receptors are single polypeptide chains that have 7 transmembrane domains and are coupled to heterotrimeric guanine-binding proteins (G proteins) consisting of 3 subunits: α, β, and γ. Hormone binding to the G protein–coupled receptor produces a conformational change that induces interaction of the receptor with the regulatory G protein, stimulating the release of guanosine diphosphate (GDP) in exchange for guanosine triphosphate (GTP), resulting in activation of the G protein (see Figure 1–5). The activated G protein (bound to GTP) dissociates from the receptor followed by dissociation of the α from the βγ subunits. The subunits activate intracellular targets, which can be either an ion channel or an enzyme. Hormones that use this type of receptor include TSH, vasopressin, or antidiuretic hormone, and catecholamines.

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The 2 main enzymes that interact with G proteins are adenylate cyclase and phospholipase C, and this selectivity of interaction is dictated by the type of G protein with which the receptor is associated. On the basis of the Gα subunit, G proteins can be classified into 4 families associated with different effector proteins. The signaling pathways of 3 of these have been extensively studied. The Gαs activates adenylate cyclase, Gαi inhibits adenylate cyclase, and Gαq activates phospholipase C; the second-messenger pathways used by Gα12 have not been completely elucidated.

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The interaction of Gαs with adenylate cyclase and its activation result in increased conversion of adenosine triphosphate to cyclic 3′,5′-adenosine monophosphate (cAMP), with the opposite response elicited by binding to Gαi-coupled receptors. The rise in intracellular cAMP activates protein kinase A, which in turn phosphorylates effector proteins, responsible for producing cellular responses. The action of cAMP is terminated by the breakdown of cAMP by the enzyme phosphodiesterase. In addition, the cascade of protein activation can also be controlled by phosphatases; which dephosphorylate proteins. Phosphorylation of proteins does not necessarily result in activation of an enzyme. In some cases, phosphorylation of a given protein results in inhibition of its activity.

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Gαq activation of phospholipase C results in the hydrolysis of phosphatidylinositol bisphosphate and the production of diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C, which phosphorylates effector proteins. IP3 binds to calcium channels in the endoplasmic reticulum, leading to an increase of Ca2+ influx into the cytosol. Ca2+ can also act as a second messenger by binding to cytosolic proteins. One important protein in mediating the effects of Ca2+ is calmodulin. Binding of Ca2+ to calmodulin results in the activation of proteins, some of which are kinases, leading to a cascade of phosphorylation of effector proteins and cellular responses. An example of a hormone that uses Ca2+ as a signaling molecule is oxytocin discussed in Chapter 2.

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Receptor Protein Tyrosine Kinases

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Receptor protein tyrosine kinases are usually single transmembrane proteins that have intrinsic enzymatic activity (Figure 1–6). Examples of hormones that use these types of receptors are insulin and growth factors. Hormone binding to these receptors activates their intracellular kinase activity, resulting in phosphorylation of tyrosine residues on the catalytic domain of the receptor itself, increasing its kinase activity. Phosphorylation outside the catalytic domain creates specific binding or docking sites for additional proteins that are recruited and activated, initiating a downstream signaling cascade. Most of these receptors consist of single polypeptides, although some, like the insulin receptor, are dimers consisting of 2 pairs of polypeptide chains.

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Figure 1–6.

Graphic Jump Location

Receptor kinase and receptor-linked kinase receptors. Receptor kinases have intrinsic tyrosine or serine kinase activity, which is activated by binding of the hormone to the amino terminal of the cell membrane receptor. The activated kinase recruits and phosphorylates downstream proteins, producing a cellular response. One hormone that uses this receptor pathway is insulin. Receptor-linked tyrosine kinase receptors do not have intrinsic activity in their intracellular domain. They are closely associated with kinases that are activated with binding of the hormone. Examples of hormones using this mechanism are growth hormone and prolactin.

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Hormone binding to cell surface receptors results in rapid activation of cytosolic proteins and cellular responses. Through protein phosphorylation, hormone binding to cell surface receptors can also alter the transcription of specific genes through the phosphorylation of transcription factors. An example of this mechanism of action is the phosphorylation of the transcription factor cyclic 3′,5′- adenosine monophosphate response element binding protein (CREB) by protein kinase A in response to receptor binding and adenylate cyclase activation. This same transcription factor (CREB) can be phosphorylated by calcium-calmodulin following hormone binding to receptor tyrosine kinase and activation of phospholipase C. Therefore, hormone binding to cell surface receptors can elicit immediate responses when the receptor is coupled to an ion channel or through the rapid phosphorylation of preformed cytosolic proteins, and it can also activate gene transcription through phosphorylation of transcription factors.

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Intracellular Receptors

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Receptors in this category belong to the steroid receptor superfamily (Figure 1–7). These receptors are transcription factors that have binding sites for the hormone (ligand) and for DNA and function as ligand (hormone)-regulated transcription factors. Hormone-receptor complex formation and binding to DNA result in either activation or repression of gene transcription. Binding to intracellular hormone receptors requires that the hormone be hydrophobic and cross the plasma membrane. Steroid hormones and the steroid derivative vitamin  D3 fulfill this requirement (see Figure 1–7). Thyroid hormones must be actively transported into the cell.

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Figure 1–7.

Graphic Jump Location

Intracellular receptors. Two general types of intracellular receptors can be identified. The unoccupied thyroid hormone receptor is bound to DNA and it represses transcription. Binding of thyroid hormone to the receptor allows for gene transcription to take place. Therefore, thyroid hormone receptor, acts as a repressor in the absence of the hormone, but hormone binding converts it to an activator that stimulates transcription of thyroid-hormone inducible genes. The steroid receptor, such as that used by estrogen, progesterone, cortisol, and aldosterone, is not able to bind to DNA in the absence of the hormone. Following steroid hormone binding to its receptor, the receptor dissociates from receptor-associated chaperone proteins. The hormone–receptor (HR) complex translocates to the nucleus, where it binds to its specific responsive element on the DNA and initiates gene transcription. (Modified with permission from Gruber et al. Mechanisms of disease: production and actions of estrogens. N Engl J Med. 2002;346(5):340. Copyright © Massachusetts Medical Society. All rights reserved.)

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The distribution of the unbound intracellular hormone receptor can be cytosolic or nuclear. Hormone-receptor complex formation with cytosolic receptors produces a conformational change that allows the hormone-receptor complex to enter the nucleus and bind to specific DNA sequences to regulate gene transcription. Once in the nucleus, the receptors regulate transcription by binding, generally as dimers, to hormone response elements normally located in regulatory regions of target genes. In all cases, hormone binding leads to a nearly complete nuclear localization of the hormone-receptor complex. Unbound intracellular receptors may be located in the nucleus, as in the case of thyroid hormone receptors. The unoccupied thyroid receptor represses transcription of genes. Binding of thyroid hormone to the receptor activates gene transcription.

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Hormone Receptor Regulation

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Hormones can influence responsiveness of the target cell by modulating receptor function. Target cells are able to detect changes in hormone signal over a very wide range of stimulus intensities. This requires the ability to undergo a reversible process of adaptation or desensitization, whereby a prolonged exposure to a hormone decreases the cells' response to that level of hormone. This allows cells to respond to changes in the concentration of a hormone (rather than to the absolute concentration of the hormone) over a very wide range of hormone concentrations. Several mechanisms can be involved in desensitization to a hormone. Hormone binding to cell-surface receptors, for example, may induce their endocytosis and temporary sequestration in endosomes. Such hormone-induced receptor endocytosis can lead to the destruction of the receptors in lysosomes, a process that leads to receptor downregulation. In other cases, desensitization results from a rapid inactivation of the receptors for example, as a result of a receptor phosphorylation. Desensitization can also be caused by a change in a protein involved in signal transduction following hormone binding to the receptor or by the production of an inhibitor that blocks the transduction process. In addition, a hormone can downregulate or decrease the expression of receptors for another hormone and reduce that hormone's effectiveness.

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Hormone receptors can also undergo upregulation. Upregulation of receptors involves an increase in the number of receptors for the particular hormone and frequently occurs when the prevailing levels of the hormone have been low for some time. The result is an increased responsiveness to the physiologic effects of the hormone at the target tissue when the levels of the hormone are restored or when an agonist to the receptor is administered. A hormone can also upregulate the receptors for another hormone, increasing the effectiveness of that hormone at its target tissue. An example of this type of interaction is the upregulation of cardiac myocyte adrenergic receptors following sustained elevations in thyroid hormone levels.

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Source: https://accessmedicine.mhmedical.com/content.aspx?bookid=507§ionid=42540501

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