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Major metabolic pathways in the brain
- in the absorptive state
- glucose-GLUT-1->glucose-glycolysis->acetyl CoA->TCA->ATP+CO2+H2O
- during fasting
- ketobodies->acetyl CoA->...
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GLUT-1 is insulin _______
insensitive
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The depolarization phase of an action potential is due to ___________; The repolarization phase of an action potential is due to ___________.
- the opening of voltage-gated sodium channels
- the opening of voltage-gated potassium channels
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Local anesthetics block __________.
- voltage-gated sodium channels
- all contain tertiary amine, which contains a positive charge under physiological pH and is involved in blocking the Na chan
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Sequential activation of gated ion channels at a neuromuscular junction
- AP at motor neuron -> voltage-gated Ca2+ chan open and Ca2+ influx -> ACh released -> ligand-gated nicotinic receptor (ionotropic) > Na+ influx, K+ efflux -> voltage-gated Na chan open -> depolarization -> Ca2+ released from ER (SR) -> contraction
- endocrine cells use similar mechanism
- Nicotine is more effective at brain
-
parasympathetic system causes reduced muscle contraction via:
- muscarinic AChR (GPCR) -> Giα binds to GTP and Gβγ binds to K chan -> K chan opens and outflow -> hyperpolarize
- epinephrine has the opposite effect
-
bacterial toxin
- cholera toxin -> prolonged activation of GsPCR -> continuous activation -> severe diarrhea
- pertussis toxin -> prolonged inactivation of GiPCR -> disable the inhibition -> whooping cough
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Parkinson disease
- • Common neurological disorder in US
- • Symptoms: paucity of spontaneous movement, tremor at rest, muscle rigidity, shuffling gait, mask-like facial expression, autonomic disturbances, depression, cognitive impairment
- • Results from degeneration of dopamine neurons in the substantia nigra pars compacta
- • Oral administration of L-DOPA was found beneficial but effects diminish >5 years (do not administer dopamine directly because it does not cross BBB; L-DOPA transporter exists)
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Benzodiazepines facilitate ______ transmission
- GABAergic
- used as anti-axiety and anesthetic
- GABA: major inhibitory neural transmitter
- At high doses, anti anxious -> unconscious
- rape drugs
-
Opiate analgesics: exert their activity by binding
- to ____ receptors in brain, which are ____.
- opioid
- GPCRs
-
inappropriate proteolytic cleavage of ___________ can lead to Alzheimer disease
- amyloid precursor protein (APP)
- normally degraded by α- and γ-secretase
- in Alzheimer, β-secretase cleaves the protein into longer-than-normal amyloid, Aβ42, which tends to aggregate and form amyloid plaque
-
Energy production in cancer cells is characterized by:
- aerobic glycolysis: the Warburg effect
- behave like normal cells in anaerobic environment, pyruvate is mostly converted to lactate and provides very little ATP compared to TCA.
-
Development of Cancer Requires ___________
- Several Mutations: the multi-hit model
- 5-6 hits before malignant cancer cells emerge
-
There is a strong relationship between the lifetime risk of cancer in a given tissue and ______________.
the number of stem cell divisions in the lifetime of that tissue
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Classes of genes implicated in the onset of cancer
- Proto-oncogene - dominant; Ras
- Tumor-suppressor gene - recessive; p53
- Caretaker genes - DNA repair
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Ras active - inactive transformation
- inactive form binds to GDP
- under the help of GEF (G exchange factor), it releases GDP and GTP, which has higher concentration than GDP, binds to it
- becomes the active form
- the GTPase function of Ras tends to convert GTP to GDP, there are signals promote or inhibit the conversion
- Ras becomes inactive again
- The oncogenic mutation of RasV12 loses the GTPase function, thus becomes permanently active
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Ras/MAPK pathway
- active Ras activates Raf
- active Raf activates MEK
- active MEK activates MAPK
- active MAPK translocates to nucleus and activates many transcription factors
-
The development of human cancer
has a defined development from benign tumor to metastasis (migrating), including accumulation of mutations
-
Effects of oncogenic mutations in proto-oncogenes that encode cell-surface receptors
after mutation the receptor becomes ligand-independent, constantly active kinase
-
chronic myelogenous leukemia (CML)
- translocation of chromosomes
- fusion Bcr-Abl protein Tyr kinase
- inhibitor, Imatinib (Gleevec), developed to specifically block the Tyr kinase and used to treat CML and some other cancers
-
p53 is a tumor suppressor and mutations of p53 are prevalent (>50%) in many cancers
- activated in response to DNA damage
- leads to apoptosis, G1 and G2 arrest, and DNA repair
- mutation -> cancer
-
Damage to DNA is unavoidable and arises in many ways:
- Spontaneous cleavage of chemical bonds in DNA
- Environmental agents: uv and ionizing radiation
- By-products of normal cell metabolism: reactive O2 species
- Environmental genotoxins
- Mistakes during DNA replication or repair
- Defects in DNA repair mechanisms and cancer are closely related
-
Point mutations in mRNA
- nonsense mutation: becomes a stop codon
- missense mutation: becomes codon of a different AA
- silent mutation: corresponds to the same AA, no effect
-
point mutation: transition vs transversion
- transition: purine->purine or pyrimidine->pyrimidine
- transversion: purine<->pyrimidine
-
____ is usually considered to be the mutated base when there is a mismatch
- T
- spontaneous deamination: Met-C -> T
-
Base excision repair of a T-G mismatch
- DNA glycosylase cleaves the glycosidic bond between the base and the sugar, removes the thymine and leaves behind the deoxyribose
- APEI (Apyrimidinic) endonuclease creates a nick
- Lyase cleaves off the sugar
- DNA Pol β fills in the gap
- DNA ligase forms the phosphodiester bond
- Oxidized bases can also be removed through this process
-
Mismatch excision repair
- some machinery recognize the mismatch
- an endonuclease makes a nick
- helicase and exonuclease together remove a segment around the error
- polymerase and ligase together fill the gap
- mutation of the recognizing machinery or the endonuclease -> hereditary nonpolyposis colorectal cancer (HNPCC)
-
Nucleotide excision repair
- adjacent T form cyclobutane w/ UV radiation
- many proteins involved in the repair, including TFIIH, which is also a transcription factor and has helicase function
- recognize->helicase+endonuclease-> segment with error removed -> polymerase and ligase repair the gap
- mutation of involved proteins genes resulted in xeroderma pigmentosum
-
Error-prone repair by nonhomologous end-joining
- when double strand breaks
- DNA-PK, KU70/KU80 dimer, and other proteins cleave short the broken ends and attach them together directly
- the new DNA is shorter than the original, last resort of DNA repair
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