Beruflich Dokumente
Kultur Dokumente
Dr V.N NDIKUM
8-Mar-12
Characteristics of a Receptors
Specificity
Affinity
Energetics of ligand receptor interactions Energetics of binding determine specificity A measure of the ability of a bound drug to activate the receptor Distinguishes agonist from antagonist Finite number of binding sites on a receptor, along with specificity of
interactions, implies that binding sites can become fully occupied with ligand molecules Additionalligand leads to non-specific binding
structure Generally, receptor binding sites are regions of the protein with a specific arrangement of charged amino acid side chains that are exposed, allowing access to the binding molecule (drug) Site must be spatially and energetically favorable for binding Binding of ligand to receptor can lead to conformational changes making further binding more favorable
interactions
Types of receptors
Types of receptors
10
11
Signal transduction
1. enzyme linked
(multiple actions)
2.
3. G protein linked
(amplifier)
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Structure: Single polypeptide chain threaded back and forth resulting in 7 transmembrane helices Theres a G protein attached to the cytoplasmic side of the membrane (functions as a switch).
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14
Signal transduction
2.
Tyrosine-kinase receptors
Structure: Receptors exist as individual polypeptides Each has an extracellular signal-binding site An intracellular tail with a number of tyrosines and a single helix spanning the membrane
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Signal transduction
3. Ion channel receptors
Structure:
Protein pores in the plasma membrane
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18
Signal transduction: Intracellular receptors Not all signal receptors are located on the
plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. The signal molecule must be able to pass through plasma membrane. Examples:
Nitric oxide (NO) Steroid
(e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).
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Second Messenger
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molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are:
1. Cycle AMP 2. Calcium ions Ca2+
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Ai
Adenylate Cyclase
R2
Gi
GTP
GTP ATP-Mg++
GDP
AMP PDE
GDP
cAMP
Protein
C Reg C Reg
C C
PKA
Protein-P
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Phospholipase C, Inositol Trisphosphate (IP3), Ca2+ and Diacylglycerol, Protein Kinase C (PKC) Ca++
A
R
Gq
PKC
Protein
IP3 Ca++
PLC phospholipase C PIP2 phosphatidylinositol bisphosphate IP3 inositol trisphosphate
Protein-P
Endoplasmic Reticulum
Ca++
Ca++
C.M.
Ca++
NO
GTP
Soluble Guanylate Cyclase
NO Synthetase
+ Citrulline GTP
NO
cGMP
Arginine
PDE
GMP
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Second messengers
Calcium Ions (Ca2+) and Inositol Trisphosphate
Calcium more widely used than cAMP used in neurotransmitters, growth factors,
some hormones Increases in Ca2+ causes many possible responses such as:
Muscle cell contraction Secretion of certain substance Cell division
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Benefits of a signal-transduction
Two benefits of a signal-transduction pathway
1. Signal amplification 2. Signal specificity
Signal amplification
Proteins persist in active form long enough
to process numerous molecules of substrate Each catalytic step activates more products than in the proceeding steps
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System acetylcholinergic
aminoacidergic
GABA receptors
glutamate ionotropic receptors glutamate metabotropic receptors
glycine receptors
histamine receptors peptidergic purinergic opioid receptors other peptide receptors adenosine receptors (P1 purinoceptors) P2 purinoceptors
408/7
Subtype
D1 D2 Gs Gi Gq/11 Gi Gi Gs
Transducer
cAMP cAMP IP3/DAG, K+, Ca2+ cAMP cAMP, K+ cAMP
Structure (aa/TM)
446/7 443/7
D3 D4 D5
Transducer cAMP
Structure 421/7
5-HT1B
5-HT1D 5-ht1E 5-ht1F
Gi/o
Gi/o Gi/o Gi/o
cAMP
cAMP cAMP cAMP
390/7
377/7 365/7 366/7
5-HT2A
5-HT2B 5-HT2C 5-HT3 5-HT4 5-ht5A 5-ht5B
Gq/11
Gq/11 Gq/11 Gs ? ?
IP3/DAG
IP3/DAG IP3/DAG cAMP
471/7
481/7 458/7 387/7 357/7 370/7
5-ht6
5-HT7
Gs
Gs
cAMP
cAMP
440/7
445/7