How Does Whooping Cough Affect G-proteins

G Proteins and Disease

G proteins function as key transducers of information across cell membranes by coupling receptors to effectors such as adenylyl cyclase (AC) or phospholipase C (see Fig. 1.9). They are part of a large family of proteins that bind and hydrolyze guanosine triphosphate (GTP) as part of an "on" and "off" switching mechanism. G proteins are het-erotrimers, consisting of Ga, Gp, and G7 subunits, each of which is encoded by a different gene.

Some strains of bacteria have developed toxins that can modify the activity of the a subunit of G proteins, resulting in disease. For example, cholera toxin, produced by the microorganism that causes cholera, Vibrio cholerae, causes ADP ribosylation of the stimulatory (Gas) subunit of G proteins. This modification abolishes the GTPase activity of Gas and results in an as subunit that is always in the "on" or active state. Thus, cholera toxin results in continuous stimulation of AC. The main cells affected by this bacterial toxin are the epithelial cells of the intestinal tract, and the excessive production of cAMP causes them to secrete chloride ions and water. This causes severe diarrhea and dehydration and may result in death.

Another toxin, pertussis toxin, is produced by Bordatella pertussis bacteria and causes whooping cough. The pertussis toxin alters the activity of Gai by ADP ribo-sylation. This modification inhibits the function of the ai subunit by preventing association with an activated receptor. Thus, the ai subunit remains GDP-bound and in an "off" state, unable to inhibit the activity of AC. The molecular mechanism by which pertussis toxin causes whooping cough is not understood.

The understanding of the actions of cholera and pertussis toxins highlights the importance of normal G-protein function and illustrates that dysfunction of this signaling pathway can cause acute disease. In the years since the discovery of these proteins, there has been an explosion of information on G proteins and several chronic human diseases have been linked to genetic mutations that cause ab normal function or expression of G proteins. These mutations can occur either in the G proteins themselves or in the receptors to which they are coupled.

Mutations in G-protein-coupled receptors (GPCRs) can result in the receptor being in an active conformation in the absence of ligand binding. This would result in sustained stimulation of G proteins. Mutations of G-protein subunits can result in either constitutive activation (e.g., continuous stimulation of effectors such as AC) or loss of activity (e.g., loss of cAMP production).

Many factors influence the observed manifestations resulting from defective G-protein signaling. These include the specific GPCRs and the G proteins that associate with them, their complex patterns of expression in different tissues, and whether the mutation is germ-line or somatic. Mutation of a ubiquitously expressed GPCR or G protein results in widespread manifestations, while mutation of a GPCR or G protein with restricted expression will result in more focused manifestations.

Somatic mutation of Gas during embryogenesis can result in the dysregulated activation of this G protein and is the source of several diseases that have multiple pleiotropic or local manifestations, depending on when the mutation occurs. For example, early somatic mutation of Gas and its overactivity can lead to McCune-Albright syndrome (MAS). The consequences of the mutant Gas in MAS are manifested in many ways, with the most common being a triad of features that includes polyostotic (affecting many bones) fibrous dysplasia, cafe-au-lait skin hy-perpigmentation, and precocious puberty. A later mutation of Gas can result in a more restricted focal syndrome, such as monostotic (affecting a single bone) fibrous dysplasia.

The complexity of the involvement of GPCR or G proteins in the pathogenesis of many human diseases is beginning to be appreciated, but already this information underscores the critical importance of understanding the molecular events involved in hormone signaling so that rational therapeutic interventions can be designed.

tracellular domain on one end of the molecule, separated by a seven-pass transmembrane-spanning region from the cytosolic regulatory domain at the other end, where the receptor interacts with the membrane-bound G protein. Binding of ligand or hormone to the extracellular domain results in a conformational change in the receptor that is transmitted to the cytosolic regulatory domain. This con-formational change allows an association of the ligand-bound, activated receptor with a trimeric G protein associated with the inner leaflet of the plasma membrane. The interaction between the ligand-bound, activated receptor and the G protein, in turn, activates the G protein, which dissociates from the receptor and transmits the signal to its effector enzyme or ion channel (Fig. 1.9).

The trimeric G proteins are named for their requirement for GTP binding and hydrolysis and have been shown to have a broad role in linking various seven-pass transmembrane receptors to membrane-bound effector systems that generate intracellular messengers. G proteins are tethered to the membrane through lipid linkage and are het-

erotrimeric, that is, composed of three distinct subunits. The subunits of a G protein are an a subunit, which binds and hydrolyzes GTP, and (P and 7 subunits, which form a stable, tight noncovalent-linked dimer. When the a subunit binds GDP, it associates with the P7 subunits to form a trimeric complex that can interact with the cytoplasmic domain of the GPCR (Fig. 1.10). The conformational change that occurs upon ligand binding causes the GDP-bound trimeric (a, (P, 7 complex) G protein to associate with the ligand-bound receptor. The association of the GDP-bound trimeric complex with the GPCR activates the exchange of GDP for GTP. Displacement of GDP by GTP is favored in cells because GTP is in higher concentration.

The displacement of GDP by GTP causes the a subunit to dissociate from the receptor and from the P7 subunits of the G protein. This exposes an effector binding site on the a subunit, which then associates with an effector molecule (e.g., adenylyl cyclase or phospholipase C) to result in the generation of second messengers (e.g., cAMP or IP3 and DAG). The hydrolysis of GTP to GDP by the a subunit re-

Hormone Adenylate Cyclase Phospholipase

Activation of a G-protein-coupled receptor and the production of cAMP. Binding of a hormone causes the interaction of the activated receptor with the inactive, GDP-bound G protein. This interaction results in activa tion of the G protein through GDP to GTP exchange and dissociation of the a and P7 subunits. The activated a subunit of the G protein can then interact with and activate the membrane protein adenylyl cyclase to catalyze the conversion of ATP to cAMP.

sults in the reassociation of the a and P7 subunits, which are then ready to repeat the cycle.

The cycling between inactive (GDP-bound) and active forms (GTP-bound) places the G proteins in the family of molecular switches, which regulate many biochemical events. When the switch is "off," the bound nucleotide is GDP. When the switch is "on," the hydrolytic enzyme (G protein) is bound to GTP, and the cleavage of GTP to GDP will reverse the switch to an "off" state. While most of the signal transduction produced by G proteins is due to the ac tivities of the a subunit, a role for P7 subunits in activating effectors during signal transduction is beginning to be appreciated. For example, P7 subunits can activate K+ channels. Therefore, both a and P7 subunits are involved in regulating physiological responses.

The catalytic activity of a G protein, which is the hydrolysis of GTP to GDP, resides in its Ga subunit. Each Ga subunit within this large protein family has an intrinsic rate of GTP hydrolysis. The intrinsic catalytic activity rate of G proteins is an important factor contributing to the amplifi-

Skeletal Musclar Activity

Effectors Effectors

Activation and inactivation of G proteins. When bound to GDP, G proteins are in an inactive state and are not associated with a receptor. Binding of a hormone to a G-protein-coupled receptor results in an association of the inactive, GDP-bound G protein with the receptor. The interaction of the GDP-bound G protein with the activated receptor results in activation of the G protein via the exchange of GDP for GTP by the a subunit. The a and P7 subunits of the activated GTP-bound G protein dissociate and can then interact with their effector proteins. The intrinsic GTPase activity in the a subunit of the G protein hy-drolyzes the bound GTP to GDP. The GDP-bound a subunit reasso-ciates with the P7 subunit to form an inactive, membrane-bound G-protein complex.

cation of the signal produced by a single molecule of ligand binding to a G-protein-coupled receptor. For example, a Ga subunit that remains active longer (slower rate of GTP hydrolysis) will continue to activate its effector for a longer period and result in greater production of second messenger.

The G proteins functionally couple receptors to several different effector molecules. Two major effector molecules that are regulated by G-protein subunits are adenylyl cyclase (AC) and phospholipase C (PLC). The association of an activated Ga subunit with AC can result in either the stimulation or the inhibition of the production of cAMP. This disparity is due to the two types of a subunit that can couple AC to cell-surface receptors. Association of an as subunit (s for stimulatory) promotes the activation of AC and production of cAMP. The association of an aj (i for inhibitory) subunit promotes the inhibition of AC and a decrease in cAMP. Thus, bidirectional regulation of adenylyl cyclase is achieved by coupling different classes of cell-surface receptors to the enzyme by either Gs or Gi (Fig. 1.11).

In addition to as and aj subunits, other isoforms of G-protein subunits have been described. For example, aq activates PLC, resulting in the production of the second messengers diacylglycerol and inositol trisphosphate. Another

^MflfflREnn^^ Stimulatory and inhibitory coupling of G

proteins to adenylyl cyclase (AC). Stimulatory (Gs) and inhibitory (Gi) G proteins couple hormone binding to the receptor with either activation or inhibition of AC. Each G protein is a trimer consisting of Ga, Gp, and G7 subunits. The Ga subunits in Gs and Gi are distinct in each and provide the specificity for either AC activation or AC inhibition. Hormones (Hs) that stimulate AC interact with "stimulatory" receptors (Rs) and are coupled to AC through stimulatory G proteins (Gs). Conversely, hormones (Hi) that inhibit AC interact with "inhibitory" receptors (Ri) that are coupled to AC through inhibitory G proteins (Gi). Intracellular levels of cAMP are modulated by the activity of phosphodiesterase (PDE), which converts cAMP to 5'AMP and turns off the signaling pathway by reducing the level of cAMP.

Ga subunit, aT or transducin, is expressed in photoreceptor tissues, and has an important role in signaling in rod cells by activation of the effector cGMP phosphodiesterase, which degrades cGMP to 5'GMP (see Chapter 4). All three sub-units of G proteins belong to large families that are expressed in different combinations in different tissues. This tissue distribution contributes to both the specificity of the transduced signal and the second messenger produced.

The Ion Channel-Linked Receptors Help Regulate the Intracellular Concentration of Specific Ions

Ion channels, found in all cells, are transmembrane proteins that cross the plasma membrane and are involved in regulating the passage of specific ions into and out of cells.

Ion channels may be opened or closed by changing the membrane potential or by the binding of ligands, such as neurotransmitters or hormones, to membrane receptors. In some cases, the receptor and ion channel are one and the same molecule. For example, at the neuromuscular junction, the neurotransmitter acetylcholine binds to a muscle membrane nicotinic cholinergic receptor that is also an ion channel. In other cases, the receptor and an ion channel are linked via a G protein, second messengers, and other downstream effector molecules, as in the muscarinic cholinergic receptor on cells innervated by parasympathetic postgan-glionic nerve fibers. Another possibility is that the ion channel is directly activated by a cyclic nucleotide, such as cGMP or cAMP, produced as a consequence of receptor activation. This mode of ion channel control is predominantly found in the sensory tissues for sight, smell, and hearing. The opening or closing of ion channels plays a key role in signaling between electrically excitable cells.

The Tyrosine Kinase Receptors Signal Through Adapter Proteins to the Mitogen-Activated Protein Kinase Pathway

Many hormones, growth factors, and cytokines signal their target cells by binding to a class of receptors that have tyrosine kinase activity and result in the phosphorylation of tyrosine residues in the receptor and other target proteins. Many of the receptors in this class of plasma membrane receptors have an intrinsic tyrosine kinase domain that is part of the cytoplasmic region of the receptor (Fig. 1.12). Another group of related receptors lacks an intrinsic tyrosine kinase but, when activated, becomes associated with a cy-toplasmic tyrosine kinase (see Fig. 1.12). This family of ty-rosine kinase receptors utilizes similar signal transduction pathways, and we discuss them together.

The tyrosine kinase receptors consist of a hormone-binding region that is exposed to the extracellular fluid. Typical agonists for these receptors include hormones (e.g., insulin), growth factors (e.g., epidermal, fibroblast, and platelet-derived growth factors), or cytokines. The cy-tokine receptors include receptors for interferons, inter-leukins (e.g., IL-1 to IL-17), tumor necrosis factor, and colony-stimulating factors (e.g., granulocyte and monocyte colony-stimulating factors).

The signaling cascades generated by the activation of tyrosine kinase receptors can result in the amplification of

Inhibitory Protein

^MflfflREnn^^ Stimulatory and inhibitory coupling of G

proteins to adenylyl cyclase (AC). Stimulatory (Gs) and inhibitory (Gi) G proteins couple hormone binding to the receptor with either activation or inhibition of AC. Each G protein is a trimer consisting of Ga, Gp, and G7 subunits. The Ga subunits in Gs and Gi are distinct in each and provide the specificity for either AC activation or AC inhibition. Hormones (Hs) that stimulate AC interact with "stimulatory" receptors (Rs) and are coupled to AC through stimulatory G proteins (Gs). Conversely, hormones (Hi) that inhibit AC interact with "inhibitory" receptors (Ri) that are coupled to AC through inhibitory G proteins (Gi). Intracellular levels of cAMP are modulated by the activity of phosphodiesterase (PDE), which converts cAMP to 5'AMP and turns off the signaling pathway by reducing the level of cAMP.

Extra cellular-domain

Transmembrane domain flffl

Tyrosine kinase domain

Disulfide bonds

Membrane

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Responses

  • Helen Abaalom
    How does whooping cough affect gproteins?
    7 years ago
  • ZULA MICHAEL
    How does pertusis affect G proteins?
    5 years ago
  • TIM
    How does whooping cough affect the g protein?
    5 years ago
  • ELISABETH
    How does whoopiung cough affect G protein?
    5 years ago
  • Ada
    How does defect in G.protein relates with cholera and whooping cough?
    4 years ago
  • cassie
    How does G PCR involves in pertusis?
    2 years ago
  • sophia theissen
    How cholera toxic affects G proteins?
    2 years ago
  • SIIRI
    What cell signalling gets affected by whooping cough?
    1 year ago
  • peter vogt
    How whooping cough affects normal functioning of the body?
    9 months ago
  • DWIGHT
    How does whooping cough affect cells simple terms?
    8 months ago
  • Bo Tuhkasaari
    How does pertussis interfere with adenyl cyclase?
    8 months ago
  • KAROLIN THALBERG
    How does pertussis toxin affect gprotein?
    8 months ago
  • lorenzo
    How does pertussis bacterium affect G proteins?
    6 months ago
  • awate
    How does whooping cough affect the function?
    3 months ago

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