Signaling at the Cell Surface - II

Cell Biology

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Llw1jyytrukpl7mpytzb 180524 s0 khurshid aqsa signaling at the cell surface ii intro
Signaling at the Cell Surface - II
Mtpvkmceqgzv2hxwprww 180524 s1 khurshid aqsa gpcr that regulate ion channels i
GPCR That Regulate Ion Channels - I
Dd5ibnyiqzowxdjptll9 180524 s2 khurshid aqsa gpcr that regulate ion channels ii
GPCR That Regulate Ion Channels - II
Vliovqvtpcgntyvydt0o 180524 s3 khurshid aqsa gpcr that activate phospholipase c i
GPCR That Activate Phospholipase C - I
Eyosridurwgyqme1wdee 180524 s4 khurshid aqsa gpcr that activate phospholipase c ii
GPCR That Activate Phospholipase C - II
Hiobcudis1aqupg9nryp 180524 s5 khurshid aqsa activation of gene transcription by gpcr
Activation of Gene Transcription by GPCR

Lecture´s Description

GPCR That Regulate Ion Channels - I

Many neurotransmitter receptors, however, are G protein–coupled receptors. The effector protein for some of these is a Na+ or K+ channel. Neurotransmitter binding to these receptors causes the associated ion channel to open or close, leading to changes in the membrane potential. Two G protein–coupled receptors that illustrate the direct and indirect mechanisms for regulating ion channels are:

  • Muscarinic Acetylcholine Receptors
  • Gt-Coupled Receptors

Binding of acetylcholine to nicotinic acetylcholine receptors in striated muscle cells generates an action potential that triggers muscle contraction. In contrast, the muscarinic acetylcholine receptors in cardiac muscle are inhibitory. Binding of acetylcholine to these receptors slows the rate of heart muscle contraction by causing a long-lived hyperpolarization of the muscle cell membrane. Human retina contains two type of photoreceptors rods and cones. Rods are stimulated by weak light. Cones are involved in color vision. The photoreceptors synapse on layer upon layer of interneurons that are innervated by different combinations of photoreceptor cells. All these signals are processed and interpreted by the part of the brain called the visual cortex. The trimeric G protein coupled to rhodopsin, often called transducin (Gt), is found only in rod cells. Activated opsin is unstable and spontaneously dissociates into its component parts. As a consequence of this depolarization, rod cells in the dark are constantly secreting neurotransmitters, and the bipolar interneurons with which they synapse are continually being stimulated.

GPCR That Regulate Ion Channels - II

The key transducing molecule linking activated opsin to the closing of cation channels in the rod-cell plasma membrane is the second messenger cyclic GMP (cGMP). The high level of cGMP present in the dark acts to keep cGMP-gated cation channels open; the light-induced decrease in cGMP leads to channel closing, membrane hyperpolarization, and reduced neurotransmitter release. cGMP phosphodiesterase is the effector protein for Gt. A single molecule of activated opsin in the disk membrane can activate 500 Gt molecules. Conversion of active Gtα·GTP back to inactive Gtα·GDP is accelerated by a GTPase-activating protein (GAP) specific for Gtα·GTP. In mammals, Gt normally remains in the active GTP-bound state for only a fraction of a second. The crystallographic structures suggest that the nucleotide-binding domain of Gtα form a surface that binds to light activated rhodopsin. Cone cells are insensitive to low levels of illumination, and the activity of rod cells is inhibited at high light levels. Thus, when we move from daylight into a dimly lighted room, we are initially blinded. Under high-light conditions, phosphorylated opsin is abundant, and activation of Gt is reduced. A second mechanism of visual adaptation appears unique to rod cells. The mechanism by which these proteins move is not yet known, but as a result of this adaptation Gt proteins are physically unable to bind activated opsin.

GPCR That Activate Phospholipase C - I

GPCR-triggered signal-transduction pathways involve several second messengers and the mechanisms by which they regulate various cellular activities. A number of these second messengers are derived from phosphatidylinositol (PI). The levels of many phosphoinositides in cells are dynamically regulated by extracellular signals, especially those that bind to receptor tyrosine kinases or cytokine receptors. The phosphoinositide PIP2 (PI 4,5-bisphosphate) binds many cytosolic proteins to the plasma membrane. Most intracellular Ca+2 ions are sequestered in the mitochondria and in the lumen of the endoplasmic reticulum (ER) and other vesicles. A small rise in cytosolic Ca+2 induces a variety of cellular responses, and thus the cytosolic concentration of Ca+2 is carefully controlled. Binding of many hormones to their cell-surface receptors on liver, fat, and other cells induces an elevation in cytosolic Ca+2 even when Ca+2 ions are absent from the surrounding extracellular fluid. IP3 binding induces opening of the channel, allowing Ca+2 ions to exit from the ER into the cytosol. Studies have revealed that a plasma membrane Ca+2 channel, called the TRP channel or the store-operated channel, opens in response to depletion of ER Ca+2 stores. In liver cells, for instance, protein kinase C helps regulate glycogen metabolism by phosphorylating and thus inhibiting glycogen synthase. Protein kinase C also phosphorylates various transcription factors; depending on the cell type.

GPCR That Activate Phospholipase C -  II

Localized increases in cytosolic Ca+2 in specific cell types are critical to its function as a second messenger. A small cytosolic protein called calmodulin, which is ubiquitous in eukaryotic cells, functions as a multipurpose switch protein that mediates many cellular effects of Ca+2 ions. One well-studied enzyme activated by the Ca+2 /calmodulin complex is myosin light chain kinase, which regulates the activity of myosin in muscle cells. Another is cAMP phosphodiesterase, the enzyme that degrades cAMP to 5-AMP and terminates its effects. The Ca+2 calmodulin complex also plays a key role in controlling the diameter of blood vessels and thus their ability to deliver oxygen to tissues. Nitro-glycerine has been used for over a century as a treatment for the intense chest pain of angina. One of the most intriguing discoveries in modern medicine is that NO, a toxic gas found in car exhaust, is in fact a natural signaling molecule. Binding of NO to the heme group in intracellular NO receptor leads to a conformational change that increases its intrinsic guanylyl cyclase activity, leading to a rise in the cGMP level. Most of the effects of cGMP are mediated by a cGMP-dependent protein kinase, also known as protein kinase G (PKG). Relaxation of vascular smooth muscle also is triggered by binding of atrial natriuretic factor (ANF) and some other peptide hormones to their receptors on smooth muscle cells.

Activation of Gene Transcription by GPCR

Intracellular signal transduction pathways can have short-term and long-term effects on the cell. Short-term effects result from modulation of the activity of pre-existing enzymes or other proteins, leading to changes in cell metabolism or function. GPCR signaling pathways also can have long-term effects owing to activation or repression of gene transcription, leading in some cases to cell proliferation. Membrane-localized tubby transcription factor is released by activation of Phospholipase C. Sequencing of the cloned tubby gene suggested that its encoded protein contains both a DNA-binding domain and a transcription-activation domain. Tubby binds tightly to PIP2, anchoring the protein to the plasma membrane. When tubby is released into the cytosol, then it enters the nucleus and activates transcription of a still unknown gene or genes. All genes regulated by cAMP contain a cis-acting DNA sequence, the cAMP-response element (CRE), that binds the phosphorylated form of a transcription factor called CRE binding (CREB) protein. GPCR β-arrestin complex activated c-Src, which activates the MAP kinase pathway and other pathways leading to transcription of genes needed for cell division. The epinephrine-induced cell proliferation results in part from GPCR-arrestin complex mediated activation of the MAP kinase cascade. The epidermal growth factor (EGF) receptor commonly trigger the MAP kinase cascade leading to cell proliferation.

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