Receptors Flashcards

Pharmacology II

1
Q

What are the three most important steps between drugs and receptors?

A

1st step - drug-receptor interaction
2nd step - chemical communication
3rd step - pharmacological effect

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2
Q

What does mean chemical communication?

A

Chemical communication is responsible for growth, development, proliferation, differentiation, tissue and organ formation, maintenance and physiological regulation. Communication can be direct or indirect, and it determines how well a cell gives or receives messages. Receptors have two domains: 1. binding domain and 2. effector domain. If receptors are too far away then we have receptor coupling.

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3
Q

What are receptors?

A

Receptors are components of cells or tissue that when bound to a drug/molecule produce a chain of chemical reactions that lead to drug’s observed effect. They are important for three things: reception, signal transduction, and response. They differ in the intracellular response they produce.

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4
Q

What is another name for ligand-gated channels and what types of ion channels do we have?

A

Ligand-gated receptors are also known as ionotropic receptors which are very fat neurotransmitters. Ion changes differ in stimuli by which they are activated. We have three types, including:
1. voltage-gated (membrane potential)
2. ligand-gated (neurotransmitter)
3. mechanically-gated (p, T, touch)

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5
Q

Explain the types of voltage-gated ion channels.

A
  1. Ca2+, they are responsible for 2n message production. They are involved in:
    a. secretion of hormones
    b. contraction of muscles
    c. activation of protein kinase
    d. initiation of signal transduction
    e. regulating gene expression
  2. Na+ and K+, stimulate neurons and skeletal muscles.
  3. Cl-, regulates pH, volume homeostasis, cell division, differentiation, and proliferation.
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6
Q

What are the three superfamilies of ligand-gated receptors?

A

a. cys-loop (5)
b. glutamate (4)
c. purinoreceptors (3)

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7
Q

Characteristics of ligand-gated receptors.

A

They are fast neurotransmitters, react in ms, do not produce an intermediate response, responsible for synapses and skeletal muscles.

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8
Q

Nicotine-Ach receptor

A

Ach binds to two binding sides (alpha subunits) at ligand-gated receptors. It causes the opening of an ion channel that is lined with negatively charged amino acids. It enables Na+ ions to pass inside the cell membrane causing muscle contraction. The same happens when nicotine binds to two binding sites on the receptor. It happens on dopamine neurons causing the production of dopamine that is responsible for addiction.

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9
Q

GABA receptors

A

GABA molecules bind to two binding sites on ligand-gated receptors. Channel opens and it is lined with negatively charged amino acids. It allows Cl- to go inside the cell membrane whereas K+ ions for outside the cell membrane. It regulates brain function, anxiety, and muscle relaxation. It has an inhibitory action used for epilepsy and spasticity.

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10
Q

NMDAR receptors

A

When glutamate binds to receptors it causes an influx of Ca2+ ions that are uptaken by postsynaptic neurons in CNS. It can cause so much Ca2+ ions entry that leads to cell death.

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11
Q

What is another name for GPCR and what kind of structure it has?

A

It is known as a serpentine receptor, which consists of three subunits (alpha, beta, and gamma). The alpha subunit has GDP bound when it is inactivated.

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12
Q

Explain GPCR.

A

Signaling molecules bind the binding domain on the receptor. After that receptor undergoes active conformation. Alpha subunit becomes activated by transforming GDP into GPT. When the alpha subunit is activated it separates from the beta/gamma subunit and binds to the target protein (enzymes), by activating it produces a second message. Beta/gamma subunits can do the same, they bind also to target protein (ion channel, protein kinase) and activate it but without the production of a second message. When GTP changes to GDP, it returns to its original inactivated state.

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13
Q

List the types of G protein targets.

A
  1. adenyl cyclase - forms cAMP
  2. phospholipase C - IP3 and DAG formation
  3. ion channels - Ca2+ and K+
  4. Rho A /Rho kinase - cell growth, development, proliferation, differentiation, smooth muscle contraction
  5. MAP kinase - cell division
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14
Q

List the types of GCPR pathways.

A
  1. Galphas - cAMP (stimulator)
  2. Galphaq - DAG/IP3 (stimulator)
  3. Galphai - cAMP (inhibitor)
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15
Q

Explain 2nd message of IP3/DAH pathway.

A

Ach binds to M3 muscarinic receptors and by undergoing activation of GPCR also activates alpha/beta/gamma subunits. When the alpha subunit is activated GDP is transformed into GDP. After that alpha subunit binds to phospholipase C and the segment of phospholipid membrane PIP2 causes the formation of DAG and IP3. Further, IP3 binds to the ion channel on ER and causes the release of Ca2+ ions into the cytoplasm. Ca2+ ions bind to the calmodulin receptors forming the Ca2+-CaM complex. It further binds to MLC kinase causing contraction of smooth muscles. On the other hand, DAG binds to protein kinase C and causes phosphorylation of the target protein in order to produce cell response. It can bind to MARCKS protein which can cause a change in cell shape or a change in gene expression through transcription factors.

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16
Q

Explain 2nd message of cAMP and cGMP.

A

The structure of cyclic nucleotides includes sugar molecules, phosphate, and nuclear bases.
Firstly, the activated alpha subunit binds to adenyl cyclase. Further, adenyl cyclase when it is activated transforms ATP into cAMP. cAMP then activates protein kinase or by phosphodiesterase causes the formation of 5’AMP. cAMP is responsible for cardiac contraction and milrinone serves as an inhibitor caused by dysrhythmic contraction. Also. cAMP can activate protein kinase A which in addition phosphorylates target proteins.
cGMP is activated by guanylate cyclase that converts GTP into cGMP. It is activated by NO action on glyceryl trinitrate. The main function is vasodilation. And further by phosphodiesterase 5’GMP is formed.

17
Q

Explain the Galphas pathway.

A

Adrenalin (sympathetic) binds to the beta1 adrenergic receptor, the receptor undergoes active conformation and activates the alpha subunit by changing ATP into cGMP. Further, Cgmp activates protein kinase A causing an increase in Ca2+ ions influx, heart rate, and contraction. For example, glucagon is GalphasPCR which causes the transformation of ATP to cAMP and activates protein kinase and proliferation of key enzymes for glycogenolysis which leads to the release of glucose by the liber.

18
Q

Explain the Galphai pathway.

A

Ach (parasympathetic) binds to the M2 muscarinic receptor undergo active conformation and activates alpha subunit by transforming GTP into GDP. Alpha subunit binds to adenyl cyclase an inactivates it at the same time inactivating Ca2+ influx, heart rate, and contraction. Same happens with alpha2 adrenergic receptor in pancreas, when adrenalin binds to it cAMP decreases resulting in decrease insulin production.

19
Q

How kinase-linked receptors can be activated?

A

They can be activated by hormones, growth factors, and cytokines, and are responsible for inflammation immune response, cell division and differentiation, and tissue repair.

20
Q

List the types of receptors.

A

They are responsible for cell division, differentiation, inflammation immune response, tissue repair, apoptosis, and immune response.
1. receptor tyrosine kinase/insulin receptor includes receptors for many growth factors including epidermal growth factor
2. cytokine receptors lack intrinsic enzyme activity, when occupied they activate various tyrosine kinases (Jak), ligands for this receptor included for example interferons.
3. receptor serine/threonine kinase includes transforming growth factor

21
Q

Result of EGFR mutation.

A
  1. prostatic cancer
  2. colon cancer
  3. breast cancer
  4. pancreatic cancer, etc.
22
Q

Explain two pathways.

A
  1. Growth factor binds to extracellular binding domain resulting in dimerization. After that, we have tyrosine autophosphorylation (of intracellular domain). SH2-domain protein (Grb2) binds to phosphorylated receptors and becomes itself phosphorylated. Further, we have activation of RAS by change of GTP to GDP and activation of Raf, Mek, MAP kinase, and various transcription factors that lead to a change in gene expression. Important for cell growth, division, and differentiation.
  2. Cytokine binds to the extracellular domain and causes dimerization of receptors and activation of Jak and after that autophosphorylation of the intracellular domain and Jak. SH2-domain protein (Stat) binds to a phosphorylated receptor and it is being phosphorylated leading to a change in gene expression. Important for immune response.
23
Q

Explain intracellular receptor.

A

Ligands for intracellular receptors include steroid hormones, thyroid hormone, and fat-soluble vitamins D and A. They can directly interact with DNA by ligand-activating transcription factor that leads to changes in gene expression.
The structure of intracellular receptors includes:
1. N-terminal domain that contains AF1 (transactivation domain)
2. DNA-binding domain (DBD)
3. C-terminal domain or ligand-binding domain (LBD)
There are two main classes:
1. class I: present in the cytoplasm and form homodimers in the presence of ligands and migrate to the nucleus. Their ligand are mainly steroid hormones
2. class II: present in the nucleus and form heterodimers with retinoid x receptor. The ligands are usually lipids (fatty acids).