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Foundations 2 > Transporters + Receptors > Flashcards

Transporters + Receptors Flashcards

1
Q

<p>GABA-a Receptors (Class of Receptor, Effect, Key Feature, Location, Drugs)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Conduct Cl- current (inhibitory)
3. Developmental Switch - developing neurons have high IC [Cl-] due to active NKCC transporter - triggers depolarizing response when developing!
4. GABA main inhibitory NT in CNS - binds between a&amp;amp;b subunits on pentamer
5. Benzodiazepines (-azepams, -azolams), Zolpidem (Ambien), Penicillin</p>

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2
Q

<p>Inward Rectifier K+ Channels (structure)</p>

A

<p>1. Conduct K influx better than efflux (more active below Ek)

2. 4 subunit tetramer (2 TM domains per) &amp;amp; 1 pore domain
3. Pore domain - pore loop, forms selectivity filter containing O atoms on AA chain - positioned to specifically mimic K+ hydration shell</p>

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3
Q

<p>Voltage-Gated K+ Channels (structure &amp;amp; 2 types of inactivation)</p>

A

<p>AKA: Outward Rectifier K+ Channels

1. conduct outward K+ better than inward (more open above Ek)
2. 4 subunit tetramer with 1 pore domain and 1 voltage sensing domain
3. VSD - 4TM regions, S4 is TM but has positive charged AA - not as lipophilic (hyperpolarized Vm - S4 moves toward IC - closes channel; depolarized Vm - S4 moves toward EC - opens channel)
4. Inactivation - N-type (N-terminus blocks selectivity filter) &amp;amp; C-type (collapse of selectivity filter)</p>

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4
Q

<p>Twin-pore K+ Channels (structure)</p>

A

<p>AKA: K+ Leak channels

1. Directionless, open to establish Vm
2. 2 subunit dimer, 2 pore domains, and the two pore loops generate ion selectivity</p>

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5
Q

<p>K-ATP Channels (structure, location, drugs)</p>

A

<p>1. ATP-sensitive K+ channels involved in triggering Insulin Secretion
2. Located in Pancreas and Smooth Muscle
3. Four pore-forming subunits with 4 sulfonylurea receptors
PANCREAS: Increased glucose = Increased metabolism = More ATP = Inhibits K-ATP channel = Vm depolarizes more easily = V-gated Ca channels can open = insulin relased
SMC: More ATP = Inhibits K-ATP = altered depolarized Vrest = V-gated Ca channels open = vasoconstriction
4. Minoxidil, Sulfonylureas</p>

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6
Q

<p>Voltage-Gated Na+ Channel (structure, location, states, drugs)</p>

A

<p>1. 4 voltage sensing domains, 4 ion selectivity channels (select partially hydrated Na ions, allow some water passage then as well)

2. Main locations - brain, muscle, heart, peripheral nerves
3. States: Activated (Open), Inactivated, Closed
4. Drugs: TTX, Local Anaesthetics</p>

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7
Q

<p>Voltage-Gated Ca++ Channels (5 types)</p>

A

<p>Similar to V-gated Na+ Channel, but selectivity pore specific for Ca++

1. L-type: Large, Long Lasting Current (Heart &amp;amp; Skeletal Muscle AP)
2. T-type: Tiny, Transient Current (Heart, Pacemaker Cells)
3. N-Type: Neuronal (Neuronal)
4. P/Q-Type: Purkinje (Neuronal)
5. R-Type: Residual (Neuronal)</p>

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8
Q

<p>HERG K+ Channels</p>

A

<p>1. Rapid Delayed Rectifier that repolarizes membrane in cardiac AP phase 3

2. Blocking HERG too much = extends AP = LQTS = pro-arrhythmic
3. All drugs must be tested for HERG blocking and QT extension after 1 antihistamine had this off-target effect and killed a bunch of people</p>

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9
Q

<p>Nicotinic ACh Receptor (Class of Receptor, Effect, Location)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Excitatory in CNS
3. Initiates APs in skeletal muscle &amp;amp; ganglionic transmission in PNS</p>

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10
Q

<p>Ligand-Gated Channels Class (Basics)</p>

A

<p>1. Fastest Signal Transduction Motif in Biology (<1/3 ms)

| 2. Agonist opens channels for ions not at equilibrium</p>

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11
Q

<p>Serotonin 5-HT3 Receptors (Class of Receptor, Effect, Location, Drugs)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Excitatory in CNS
3. Causes emesis/activity in GI tract
4. -setrons drugs</p>

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12
Q

<p>Glycine Receptors (Class, Effect, Location, Drugs, Diseases)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Inhibitory in CNS (Cl- Channels)
3. Main inhibitory NT in SC (only NT that acts exclusively on LGIC and not on GPCRs)
4. Strychnine, Tetanus Toxin
5. Hyperekplexia</p>

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13
Q

<p>NMDA Receptors (Class, Subtype, Effect, Location, Features, Drugs, Diseases)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Glutamate-gated Ca++ channels
3. Excitatory
4. Medicate learning/memory when normal/high Ca++ in cell; medicate excitotoxicity &amp;amp; implicated in ALZHEIMER'S when excess Ca++ enters cell
5. at rest: Mg2+ stuck &amp;amp; blocks channel, needs other receptors (AMPA) to depolarize Vm to free Mg2+ and allow Ca2+ influx
6. Ca influx from receptor increases AMPA expression/sensitivity - induces learning
7. Drugs: Memanite
8. Diseases: Alzeheimer's in excess Ca2+</p>

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14
Q

<p>non-NMDA related receptors (Class, Subtype, Effect, Location)</p>

A

<p>1. Ligand-Gated Ion Channel

2. Glutamate-Gated Na+ Channels
3. AMPA - excitatory; Kainate - balancing effect - not important
4. AMPA: medicates fast excitatory transmission in CNS; FASTEST DESENSITIZATION</p>

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15
Q

<p>Overview of GPCR Signalling (Types, Components, Sequence)</p>

A

<p>1. Largest family of receptors targeted by drugs (all effectors in ANS, muscarinic ACh receptors, GABA-b, mGluRs, catecholamines, adenosine, opioid receptors)

2. a - receptor that binds agonist (heptahelical serpentine structure) &amp;amp; b - GTP binding protein (GDP binds to a-subunit, and b&amp;amp;g-subunit hold a)
3. When agonist binds receptor, conformation change, interacts with G-protein, puts on GTP takes off GDP, GTP-Ga dissociates (2nd msgr synthesis), B/G-subunit generally inhibit cell function. Termination when GTP hydrolyzes to GDP - subunits reunite</p>

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16
Q

<p>Membrane-Delimited GPCR (Timing, Effect, What each components do, Nomenclature)</p>

A

<p>1. 2nd fastest biological signaling technique (30-50ms)

2. Generic Inhibitory Motif
3. G-b/g subunits alter behavior of ion channels (activates K and closes Ca for less cell excitability)
4. G-ai subunit inhibits adenylyl cyclase = less cAMP production = less cell excitability and NT release
5. Subscript of 2 or B</p>

17
Q

<p>GPCRs - Synthesis of Secondary Messengers (Time, 2 Primary Roles, Nomenclature)</p>

A

<p>1. 3rd fastest signaling, (seconds)

2. Smooth Muscle Contraction: GTP-a activates phospholipase C, converts PIP2 to IP3, releases Ca2+ from storage sites - muscle contraction
3. PKA Activation: beta-agonist activates GTP-as activates adenylyl cyclase - increases cAMP - activates PKA
4. Subscript of 1 or odd number</p>

18
Q

<p>GPCRs - Protein Phosphorylation</p>

A

<p>1. 4th fastest signaling, (minutes) - need time to activate proteins

2. Activated PKA - phosphorylates proteins
3. beta-1: contraction of cardiac muscles
4. beta-2: relaxation of smooth muscle
5. Termination when phosphatases deactivate proteins or phosphodiesterase turns cAMP into AMP</p>

19
Q

<p>Receptor Tyrosine Kinases Class (Type, Sequence)</p>

A

<p>1. Transmembrane Enzyme Signalling
2. EC ligand binding causes RTK subunits to DIMERIZE, transphosphorylate each other, recruit SCAFFOLDING PROTEIN, gets phosphorylates and initiakes KINASE KINASE KINASE REACTIONS, last kinase activates transcription factor, alters gene behavior and triggers biological response</p>

20
Q

<p>Growth Factor Receptors (Type, Sequence, Good and Bad uses)</p>

A

<p>1. All GF receptors are RTKs

2. GF - RTK (DIMERIZES) - Scaffold GRB2 with attached SOS - converts Ras-GDP to GTP active form. Ras activates RAF (MAPKKK) activates MEK (MAPKK) activates ERK (MAPK) alters gene transcription, cell proliferation/adhesion/migration (don't need to know precise names)
3. Good: wound healing. Bad: contribute to cancer metastases</p>

21
Q

<p>Insulin Receptors (Type, Function of Insulin, Sequence)</p>

A

<p>1. Binds RTKs

2. Released in response to elevated blood glucose
3. Insulin RTKs pre-dimerized, insulin binding recruits SCAFFOLDING IRS
3a. RAS/MAPK pathway for cell growth
3b. IRS - PI-3-K - AKT (PKB) - mTOR - changes mRNA TRANSLATION - improved metabolism (better storage of fuels)</p>

22
Q

<p>Cytokine Signaling Pathway (Type, Cytokine Function, Pathway, Good/Bad uses)</p>

A

<p>1. Transmembrane Receptor (Technically not RTK)

2. interferons (IFNs) &amp;amp; interleukins (ILs) are chemical coordinators of immune response
3. JAK/STAT pathway: cytokines bind receptor - receptor dimerizes - JAK (cytoplasmic kinase, pre-bound scaffold) pre-attached to receptor, when dimerized, transphosphorylation - phosphorylated JAK recruits STAT - STATs phosphorylate and dissociate and dimerize with each other - STAT dimers alter gene transcription and coordinate immune response
4. Good: enhance wound healing; Bad: constitutive IL production = rheumatoid arthritis and some cancers</p>

23
Q

<p>Cytoplasmic/Nuclear Receptors (Ligand, Sequence, Drugs)</p>

A

<p>1. Glucocorticoids - steroids can diffuse through bilayer

2. Glucocorticoid binds receptor in cytosol - HSP-90 (endogenous inhibitor) dissociates - activated receptor complex dimerizes, goes to nucleus - changes gene transcription - inhibits inflammatory response
3. Drugs with a -son- or -one (fluticasone)</p>

24
Q

Receptor Desensitization (Tachyphylaxis, Ligand-Gated Ion Channels, GPCRs, RTKs/JAK-STATs, GC Receptors)

A
  1. Tachyphylaxis - declined responses to acute repeated injections within shortened interval (receptors desensitize)
  2. L-G IC desensitize fastest (AMPA in 1 PSP) due to channel conformational change
  3. GPCRs: activated GPCRs can be phosphorylated by GRKs (G-protein receptor kinases), which improves Beta-arrestin binding - B-arrestin (mimicks scaffold): phase 1 (blocks GPCR response) + phase 2 (causes GPCR internalization - phosphatases can help GPCR resensitize)
  4. RTKs/JAK-STATs receptors get internalized with repeated stimulation
  5. GC Receptor internalized & decreased receptor transcription
25
Q

Receptor Desensitization - Properties of Competitive Antagonists and Allosteric Agents

A
  1. Competitive Antagonists: continual use causes receptor upregulation (less sensitive to antagonist)
  2. Allosteric activators - don’t stimulate the receptor alone, results in reduced likelihood of receptor desensitization
26
Q

ABC Transporters (Name, Function)

A
  1. ATP Binding Casette

2. Mediate ATP-dependent primary active transport (some mediate anticancer drug resistance)

27
Q

p-glycoprotein (Type, Function, Bad Results)*

A
  1. ATP binding Casette
  2. eliminate drugs in the brain (prevents BBB transport); reduce GI absorption in gut epithelia (opposes reabsorption); increases secretion/excretion of drugs in bile/urine
  3. cancers develop chemotherapy resistance by expressing these - enables cells to pump drugs back out - causes tumor relapse/recurrence
  4. INDUCED BY ST. JOHN’S WORT
28
Q

SLC Transporters (Name, Function, Limitations)

A
  1. SoLute Carrier Transporters (secondary active transporters)
  2. Medicate co-transport + facilitated diffusion; substrate binding induces conformation change, creates access for substrate to go to other side - alternating access
  3. Coupled co-transport requires 2 substances to selectively bind to evoke conformational change & can be saturated because they do not require energy (need event of substrate binding to occur)
29
Q

SLC6A2, SLC6A3, SLC6A4 (Name, Function)

A
  1. All examples of SLC secondary active transporters

2. Norep, dopamine, serotonin reuptake transporters from synaptic cleft on presynaptic terminal

30
Q

H2 Histamine Receptors (Function, Activators, Drugs)

A
  1. paracrine cell in GI tract secretes histamine due to ACh/Gastrin stimulation (from a meal or pyloric distention); histamine binds parietal cell in stomach to secrete HCl
  2. Cimetidine is competitive inhibitor of H2 histamine receptor

Foundations 2 (12 decks)

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