In section II the structures of some membrane receptors were described, along with the fact that in order to deliver its message to the cell, the hormone has to cause the receptor to change so that it generates a change within the cell. In this section we will consider what some of those intracellular changes are and how they initiate a series of events that will bring about a change in the cell’s activity, the biological response to the hormone. The realm of intracellular signaling is vast and it will be necessary for us to focus our attention on the portions of systems that are encountered most frequently in the study of hormones.

1. G Protein-Coupled Receptors

As discussed in section II.B, a heterotrimeric G-protein that has GDP bound to its α-subunit is inactive. As illustrated in Figure 1, when a ligand binds to a GPCR, the receptor changes conformation and interacts with an adjacent G-protein in such a way that the latter exchanges its GDP for a GTP, thus activating the α-subunit. That is, the receptor acts as the guanine nucleotide exchange factor (GEF) that activates this particular G-protein. Different activated α-subunits have different activities. The human genome encodes 16 different α-subunits, along with 5 β- and 14 γ-subunits. β/γ-sub units appear to be mostly interchangeable with regard to their interactions with α-subunits, but it is now also recognized that these two proteins have some activities of their own, either as a dimer or individually. We will only be concerned with the activities of the α-subunits in the following discussion. Events downstream of the signaling pathways are not presented in detail here, but do appear in the chapters dealing with specific hormonal systems.

Fig1. G-protein coupled receptors (GPCRs). A. General structure of GPCRs. The G protein-coupled receptors comprise a large family of proteins that share the main structural features shown in the left side of panel A. The predominant characteristic of these proteins is the arrangement of their single polypeptide chains into seven membrane spanning regions, creating three extracellular and three intracellular loops. One or more sites on the intracellular C-terminal portion of the cell may be palmitoylated, which plays a role in the receptor’s position in the membrane. The right-hand side of panel A shows examples of the heterogeneity of the N-terminal portion of GPCRs, reflecting the diversity of ligands for these proteins. Top left: small molecules such as catecholamines or eicosanoids bind to a pocket within the membrane spanning helices; top right, small peptides are partially within a binding pocket but also interact with the extracellular portion of the receptor; bottom, large glycoproteins such as the gonadotrophins or growth factors have binding sites created by the structure of the extracellular portion of the receptor. B. Receptor interaction with G-protein. Inactive G-proteins (left) consist of three subunits in a heterotrimer, α, β, and γ. Two of the subunits, α and γ, have lipid moieties binding them to the membrane and GDP is bound to the α-subunit. When a ligand binds to the receptor and activates it, GDP is replaced with GTP; the α-subunit dissociates from the trimer and moves through the membrane to a nearby protein, an enzyme or ion channel, for example, and activates it, initiating the biological response (see Figure 3).

Figure 2 shows the outcome of receptor-initiated G-protein activation in the case of the three types of α-subunits that will be encountered most frequently in this book. On the left are Gsα and Giα. These proteins interact with the membrane enzyme adenylyl cyclase, which converts one molecule of ATP into one of cyclic AMP (adenosine-3′-5′-cyclic monophosphate) the first intracellular second message to be discovered in the 1970s. Cyclic AMP binds to the regulatory subunits of PKA (cyclic AMP-dependent protein kinase) causing the catalytic subunits to become active. At this point the pathway can go in one of several directions, depending on the cell type. All outcomes are dependent on the phosphorylation of protein substrates at specific serine or threonine residues by the activated PKA. Four of these are shown in Figure2, illustrating the diversity of possible responses to this second messenger, including changes in ion transport, in gene transcription, and in the activity of existing enzyme proteins. The activity of target proteins might be either increased or decreased by phosphorylation. An extracellular signaling agent that triggers the activation of a Giα protein will have the opposite effect on a pathway that is stimulated by Gsα.

Fig2. Hormonal signaling by G-protein coupled receptors. Two of the most common signaling pathways used by GPCRs are illustrated, those initiated by Gsα, Giα, and Gqα. These three G-proteins are each the most widely distributed members of the three subfamilies of G-proteins which bear the names Gsα, Gi/oα, and Gq/11α, respectively. Sometimes the abbreviations of the proteins will have a different order of the α and the subfamily, s, i, or q. In Figure 1 the G-protein molecules are shown after being released from their βγ partners through interaction with a G-protein coupled receptor (see Figure 1). As shown in this figure Gsα and Giα stimulate or inhibit, respectively, adenylyl cyclase in the plasma membrane, bringing about an increase or decrease in this second messenger within the cell. When levels of cAMP rise, PKA (cyclic AMP-dependent protein kinase) is activated. Depending on the cell type, one or more steps of activation (or in some cases inactivation) ensue, some of which may involve additional phosphorylation events. Examples of these include the opening of ion channels in the cell membrane, phosphorylation of the transcription factor CREB (cyclic AMP response element binding protein), activation or inhibition of enzymatic steps in the metabolism of glycolysis or lipids. On the right side of the figure, Gqα, also released from a receptor-G-protein complex, activates phospholipase C, which catalyzes the release of two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). See Figure 3 for the details of this reaction. DAG activates protein kinase C, which can activate one of several targets, in this example Raf, which allows entry to the MAPK pathway or the transcription factor NFκB to affect gene transcription.

On the right side of Figure 2 Gqα is shown inter acting with phospholipase C. This enzyme catalyzes the reaction shown in Figure 3, the hydrolysis of the membrane lipid phosphatidyl inositol 4,5-bis-phosphate into IP3 (inositol 1,4,5-triphosphate) and diacylglyde rol (DAG), each of which are second messengers. DAG is necessary for the activation of protein kinase C and IP3 activates the release of Ca2+ from intracellular stores in the endoplasmic reticulum. This divalent cation acts as yet another second messenger with many possible actions in the cell, including the stimulation, along with DAG, of protein kinase C. Targets for protein kinase C include the phosphorylation and augmentation of enzymes in the MAP kinase pathway and the phosphorylation of the nuclear transcription factor NFκB. The increased intracellular Ca2+ may activate exocytosis, the basis of the Ca2+ secretion coupling mechanism often associated with the secretion of peptide hormones by their secretory glands, for example pituitary hormones and insulin.

Fig3. Phospholipase C reaction. The cleavage by phospholipase C of phosphatidyl inositol 4,5-bisphosphonate into diacylglycerol (DAG) and inositol 1,4,5,-triphosphate (IP3) is shown.

Ca2+ may also bind to calmodulin, a 17kDa calcium sensing protein. Calmodulin is present in the cytoplasmic compartment of virtually all cells of higher organisms.

It binds four Ca2+ ions tightly (Kd ≅ 10−8 M) and then undergoes a conformational change so that it interacts with a number of Ca2+-regulated proteins. These include Ca2+-calmodulin-dependent protein kinases, Ca2+-ATPase (a Ca2+ pump), myosin light chain kinase, and phosphatidyl inositol-3-kinase, to name a few.

Regardless of the type of activated G-protein α-sub unit, the GTP bound to the α-subunit is soon hydrolyzed to GDP. The α-subunit is inactivated and binds again to the βγ-subunits, turning off the signal. The speed with which the signal is turned off may be modulated by nearby proteins called GTP-ase activating (or accelerating) proteins, or GAPs. These proteins can, in turn, be regulated both positively and negatively by other signaling systems. This is an example of one type of cross talk between signaling pathways.

One important feature of signaling pathways initiated by membrane receptors, their amplification, or cascade property, is exemplified by one of the first of the path ways to be elucidated, the cAMP mediated control of glycogen breakdown in the skeletal muscle. As depicted in Figure 4 several steps in the cascade (indicated by the stars) allow for, at the very minimum, amplification of 1–2 orders of magnitude because of the catalytic nature of the event. Thus, a rapid robust response can be obtained from a fairly small change in the concentration of circulating hormone. This is a general feature of mem brane initiated signaling events that involve one or more catalytic events. A higher order cascade is seen in hormonal systems that involve the central nervous system, hypothalamus, pituitary, and peripheral target organ.

Fig4. Amplification of hormonal signaling. The cascade of events from the binding of epinephrine to its G-protein coupled receptor in skeletal muscle to the breakdown of glycogen is shown as one example of the amplification of hormonal signaling. On the left are molecules that are inactive in the cascade prior to the initial binding event and on the right are the active forms of the molecules. As shown in Figures 1 and 2, Gsα is activated by hormone binding and in turn activates adenylyl cyclase in the membrane, generating the second messenger cAMP. Protein kinase A (cyclic AMP dependent protein kinase, PKA) phosphorylates and activates glycogen phosphorylase kinase (phosphorylase kinase), which phosphorylates and activates glycogen phosphorylase. The phosphorylation of glycogen initiates its breakdown into, ultimately, glucose, which is used for the energy needs of the muscle cell. At the steps with a gold star, one activated molecule may generate 10–100 (or more) active molecules. Thus the signal from one occupied GPCR can be amplified several-fold, allowing for a large rapid response to a small signal.

2. Receptor Tyrosine Kinases

Figure 5 illustrates three of the main signaling pathways used by receptor tyrosine kinases. On the right is the MAP kinase cascade with three tiers of activation beginning with that of the kinase Raf (MAPKKK) by a small G-protein, Ras. Ras in turn is activated by the guanine nucleotide exchange factor, SOS, recruited to the phosphorylated RTK by the adaptor protein GRB2.

Fig5. Receptor tyrosine kinase (RTK) signaling. The active form of an RTK is a dimer that is formed either before or as the ligand binds. Such an activated form is depicted here (purple). The extracellular ligand binding/dimerization brings about a conformational change in the receptor protein that conveys the message to the intracellular portion of the receptor. Tyrosine kinase (dark purple) is activated and autophosphorylates the cytoplasmic portion of the receptor (blue circles). This leads to interaction of the receptor with other intracellular transducing enzymes such as phospholipase C, leading to activation of PKC (see Figure 2) or PI3 kinase which phosphorylates and activates AKT (protein kinase B). Protein kinases B and C phosphorylate and activate proteins involved in the downstream effects of the hormone, including transcription factors. On the right is shown the activation of the MAP kinase (mitogen activated protein kinase) pathway through the adaptor protein GRB2, the guanine nucleotide exchange factor SOS, and activation of the small G-protein, Ras. This leads to the cascade of activation of Raf (MAPKKK), MAP kinase kinase (MAPKK), and MAP kinase (ERK1/2), which can phosphorylate cytoplasmic proteins and nuclear transcription factors. PI3K, phosphatidyl inositol-3 kinase; PDK, phosphoinositide-dependent kinase; AKT, protein kinase B.

The phosphorylation of the cytoplasmic domain of the RTKs can also activate the PLCγ/protein kinase C pathway described in Figure 2. In addition, phosphatidyl inositol (PI) 3-kinase (PI3K) adds a phosphate group to the 3-position of phosphatidylinositol-4,5, -bis-phosphonate, resulting in the triphosphorylated polar head group PI-3,4,5-triphosphate, which activates phosphoinositide-dependent kinase (PDK). This protein kinase activates AKT, also known as protein kinase B, which phosphorylates nuclear transcription factors.

Note that these pathways share the same cascade property as that described in Figure 4, with amplification at each catalytic phosphorylation step. Also as with the GPCR pathways described above, the RTK pathways are subject to termination in order to limit the timing and size of the signal. Protein phosphatases, often subject to their own regulatory systems, are available to remove the activating phosphate groups to provide this termination function.

Although the GPCR and RTK pathways are responsible for transmitting many of the hormonal signals to be encountered in this book, there are others that are less frequently encountered, but no less important to the system in which they play a role. These include the JAK/STAT pathway, which is described in connection with growth hormone in Chapter 3; the guanyl cyclase pathway that mediates the actions of ANF as described in Chapter 10; and the Smad pathway of TGFβ in Chapter 17.

اخر الاخبار

اخبار العتبة العباسية المقدسة

معهد القرآن الكريم النسوي يقيم مجلس عزاء بذكرى وفاة السيدة زينب (عليها السلام)

قسم الشؤون الفكرية يقدم محاضرة توعوية لمجموعة من طلبة مدارس بغداد

قسم الشؤون الدينية يواصل إقامة محاضراته الفقهية في صحن مرقد أبي الفضل العباس (عليه السلام)

أكاديمية التطوير الإداري تنظم دورة في أمن المعلومات واستخدام تطبيقات الذكاء الاصطناعي

المزيد

الآخبار الصحية

طبيب يكشف أفضل مكمل غذائي لتحسين المزاج ودعم الصحة النفسية

دراسة جديدة تكشف أضرار الأطعمة الجاهزة على القلب ؟

6 أطعمة طبيعية تهدئ الزكام دون أدوية.. تعرف عليهم

ماذا يحدث لأعراض الزكام عند تناول الثوم بانتظام؟

المزيد

الآخبار التكنلوجية

ابتكار ثوري في بطاريات السيارات الكهربائية.. سعة أعلى 4 مرات

ماذا يحدث لجسمك عند شرب الماء الساخن يوميا؟

7 فوائد "خفية" لشرب شاي الكركديه كل يوم

دراسة تكشف قدرة الحيتان على سماع الأصوات منخفضة وعالية التردد من مسافة بعيدة

المزيد

مواضيع ذات صلة

Biosynthesis of Peptide and Protein Hormones

Hormones and Their Communication Systems

Stepwise development of tissue- specific insulin resistance

Insulin resistance in adipose tissue Adipose tissue

Insulin resistance in the liver

Insulin resistance in skeletal muscle

Insulin resistance as a risk factor for type 2 diabetes

Definition and measurement of insulin resistance in humans

Hypoglycemia without Diabetes

Diabetes heterogeneity

Targeting the brain to restore normoglycaemia

Blood Glucose Regulation