This is my notes which I wrote as I was taking a video lecture which is originated from https://www.youtube.com/watch?v=-qMSF0pz1bA&list=PLWEQK2NI_UhL5cT7AcvGYknIEkazdTVQw ================================================================================ Endoplasmic reticulum has 2 kinds: Smooth Endoplasmic reticulum Rough Endoplasmic reticulum Center circle shape: nuclei Object around nuclei: Rough Endoplasmic reticulum Red dots on Rough Endoplasmic reticulum: ribosome Green line: microtubule (like highway) Red lines around green line: actin (like roads up to the home) alzheimer's disease: damaged on green line highway Cancer: imbalance in microtubule and actin. If highway grows continuously without removing old ones, it becomes the cancer. ================================================================================ Object Rough Endoplasmic reticulum: Golgi complex which had been found by C. Golgi. Partial area of Golgi complex enters into end of body: There are also microtubule (green) and actin (red) around Golgi complex ================================================================================ Let's zoom in Rough Endoplasmic reticulum ribosome: Small small unit, Large small unit ================================================================================ Green line across ribosome: mRNA Green curved dots: which pharmacy compnay want to know because they can control the effect of drug if they know it. Green dots embeds into membrane, and they becomes various ionic channel. NR1: colored one NR2: non-colored one ================================================================================ Rough Endoplasmic reticulum which has ionic channel becomes separated into individual ones. Separated Rough Endoplasmic reticulum forms trans golgi network (TGN) ================================================================================ TGN can go to the end of body with delivering ionic channel into end of body ================================================================================ Ionic channel is delivered through green line (highway, microtubule) and red line (small roads, actin) Kinesin: truck that delivers ionic channel. ================================================================================ There is mLin complex on the truck Kinesin. There are ionic channel on the mLin complex Ionic channel is wrapped by separated Rough Endoplasmic reticulum ================================================================================ Myosin: Small truck on the small road (red line) Adapter on the myosin: Rab There are ionic channel wrapped by Rough Endoplasmic reticulum on the Rab ================================================================================ Let's zoom in "very end" where synapse is formed. ================================================================================ postsynaptic membrane It has phospholipid bilayer exocyst (exo: exist=exodus, cyst: pocket, which means tool which is need when being existed), scafold, ionic channel, separated Rough Endoplasmic reticulum, snare complex ================================================================================ Above complex object is embeded into phospholipid bilayer of postsynaptic membrane ================================================================================ Embeded ionic channel moves into end of postsynaptic membrane But note that ionic channel has tail Overview: ================================================================================ Under the tails, there are scafold: ================================================================================ Under the scaffold, there are GKAP protein GKAP: guanylate kinase associated protein In molecular biology, P generally stands for protein or phosphorous K generally stands for Kinase which attaches phosphorous to supply energy for molecular mechanism. phosphatase: deattaches phosphorous ================================================================================ One is the spar along with 2 GKAPs Small protein next to spar is cript ================================================================================ Colored one: NR1 Noncolored one: NR2 NR1 and NR2 are sub units which consist of NMDAR ================================================================================ Since there are scaffold, AMPAR can stand on it. ================================================================================ There are stargazin protein next to AMPA-R ================================================================================ There are CAMK2 (Ca2+ calmodulin Kinase 2, 20 nanometer) next to tail of ionic channel Path width of AMPAR, NMDAR is 10 nano meter ================================================================================ calmodulin protein absorbs calcium, not make cells as like bone ================================================================================ mGluR: protein, glutamate receptor ================================================================================ Shank protein and Hemer are attached onto GKAP Shank protein is composed of src homology and anklyn protein ================================================================================ Homer has calciumn reservoir which has phospholipid bilayer Door of calciumn reservoir is called IP_3 R (inositol triphosphate) ================================================================================ If signal comes from center ionic channel, that signal is passed and it opens IP_3 R ================================================================================ mGluR has 2 Homers, and shank, cortactin protein, and red line (actin) Calcium reservoir is linked by Rab and myosin ================================================================================ There is SynGAP (Syn means synaptic) protein next to GKAP ================================================================================ There is Fyn protein next to tail ================================================================================ presynaptic membrane generally has pockets as well as small quantity of protein postsynaptic membrane generally has large quantity of protein ================================================================================ n methyl d aspartate receptor ================================================================================ $$$Ca^{2+}$$$ enters through NMDAR By trigger of $$$Ca^{2+}$$$, adenylyl cyclase activates cyclase forms cyclic object cyclase triggers cAMP Protein kinase A is activated by cAMP PKA inserts AMPAR ================================================================================ $$$Ca^{2+}$$$ activates $$$PYK_2$$$ (protein tyrosin kinase 2) $$$PYK_2$$$ activates Src (which is gene which promotes sarcoma) protein Src activates NMDAR ================================================================================ $$$Ca^{2+}$$$ activates $$$PKC$$$ (protein kinase C) PKC activates $$$PYK_2$$$ PKC inhibits AMPAR ================================================================================ $$$Ca^{2+}$$$ activates CaMK2 CaMK2 promotes generating AMPAR ================================================================================ cAMP triggers RapGEF protein RapGEF decomposes into Rap And Rap is regularted by Spar ================================================================================ $$$Ca^{2+}$$$ and PYK2 trigger RasGEF RasGEF decomposes into Ras protein which is cancer protein and switch protein ================================================================================ Ras activates PI3K which is enzyem which attach phosphorous into 3rd location in benzen ring of phosphatidyl inositol PI3K promotes generating AMPAR ================================================================================ SynGAP regulates Ras ================================================================================ Ras activates Raf Raf activates MEK1,2 MEK1,2 activate ERK1,2 ================================================================================ ERK1,2 enter into nuclus Activity triggers gene and DNA DNA triggers RNA (transcription) RNA performs translation into proteins ================================================================================ Proteins are delivered via Rough Endoplasmic reticulum to insert ionic channel ================================================================================ Morphology of spine changes (thinker) It's memory ================================================================================ When mGluR is attached by glutamate, mGluR creates $$$G_{\alpha}$$$ ================================================================================ $$$G_{\alpha}$$$ triggers PLC (phosphorous lipaze C) PLC opens $$$IP_{3}R$$$ $$$IP_{3}R$$$ releases $$$Ca^{2+}$$$ ================================================================================ $$$Ca^{2+}$$$ triggers PP2B PP2B triggers PP1 PP1 regulates AMPAR ================================================================================ ================================================================================ NE: norepinephrine E: epinephrine DA: dophamine SHT: serotonine Ach: acetylcholine NE, DA, SHT: metabolic Channel ionic: instant response metabolic: slow mechanism ================================================================================ glutamate: +, accelator GABA: -, brake ================================================================================ receptor for glutamate: AMPAR, NMDAR ================================================================================ Ionic receptors Glu: glutamate amino acid which is used as neurotransmitter Glu receptor AMPAR -> GluR1 - GluR4 NMDAR -> NR1 (NR1 has 8 variations) (NR1-1a NR1-2a NR1-3a NR1-4a NR1-1b NR1-2b NR1-3b NR1-4b) NR2A - NR2D (NR2C is abundant in the cerebellum) (NR2D receptor shows at initial time of generation) NR3A - NR3B 8+4+2=14 Kainate - Glu5 - Glu7, Ka1, Ka2 GABA has submodules as channels -> $$$\alpha, \beta, \gamma, \delta, \epsilon, \rho$$$ acetylcholine has channels -> $$$\alpha, \beta, \gamma, \delta$$$ nicotinic receptor has n in front of name so nAch ================================================================================ Metabolic receptors mGluR: metabolic receptors for glutamate - mGluR1 - mGluR8 metabolic receptors for GABA - GABA_A, GABA_B metabolic receptors for dophamine - D1 - D5 metabolic receptors for norepinephrine and epinephrine $$$\alpha1, \alpha2, \beta1, \beta2, \beta3$$$ metabolic receptors for serotonine (5HT) $$$5HT_1 - 5HT_7$$$ ================================================================================ Spine Dendrite GluR2, GluR3 GluR2 is attached by protein named AP2 Then, area becomes collapsed like this; ================================================================================ This is called endocytosis ================================================================================ GluR1 has long tail Suppose there is GluR3 next to GluR1 They are uploaded onto membrane CaMK2 and PI3K help them to be uploaded ================================================================================ And they're inserted into membrane ================================================================================ stargazin helps them to upload onto end of spine ================================================================================ GluR2 and GluR3 are moved into center area and it waits for "activity dependence" If there is no activity dependence, it's deleted (degradation) by lysosome by using strong acid ================================================================================ When density of NSF protein increases, it moves up ================================================================================ Red intervals: region where alternative splicing occurs Red dot: region where RNA editing happens ================================================================================ alternative splicing In RNA, there are active regions which create proteins There are many possible combinations to create protein ================================================================================ ================================================================================ * Spine * Red verticals: scaffold inside of spines ================================================================================ * Cocaine is inserted * Spines become thicker and larger * LTP (Long Term Potentation): electrical pulses are kept * Many mechanisms happen under the spines ================================================================================ * alzheimer is LTD (Long Term Declaration) ================================================================================ * scaffold is important because it's ground for mechanisms ================================================================================ * Glutamate based sysnase * GABA based synapse * gephyrin: scaffold for GABA based synapse ================================================================================ * Physiological (ordinary state) * Acute cocaine (sudden addiction to cocaine) ================================================================================ * NMDAR: NR1, NR2B ================================================================================ NR2B has tail At the end of tail, it has YEKL amino acid order Y: tyrosin E: Glutamate K: L: Lysin ================================================================================ NR1 and NR2B moves to down Space is cut by dyynamin protein ================================================================================ There is protein called clathrin like a pincet https://www.youtube.com/watch?v=-qMSF0pz1bA&list=PLWEQK2NI_UhL5cT7AcvGYknIEkazdTVQw ================================================================================ Let's see the state of those who is addicted to Cocain, at spine level ================================================================================ ORX1 receptor Cocain molecule is attached to ORX1 ================================================================================ ORX1 triggers PLC ================================================================================ NR1 (blue bar) small NR2A (red bar) very much ================================================================================ Many NR2A goes up to the membrane ================================================================================ 2B channel becomes many, which is the definition of the addiction ================================================================================ View Alzheimer at spine level Alzheimer is highly related to hippocampus ================================================================================ nAch Receptor ================================================================================ Ligand (red dot) as beta amyloid is attached to nAch-R beta amyloid: Membrane insert protein beta amyloid is cut, cut beta amyloid works as ligand ================================================================================ $$$Ca^{2+}$$$ is in ================================================================================ $$$Ca^{2+}$$$ triggers PP2B ================================================================================ STEP protein is generated STEP removes P from the protein, specifically, NR2B This process is proceeded within 10 minutes ================================================================================ You can see the red P ================================================================================ P is removed by STEP ================================================================================ AP2 is attached ================================================================================ Channel moves Number of 2B reduces ================================================================================ 2B is detached by clatin lysosome degradation occurs ================================================================================ View Schizophrenia at spine level Schizophrenia is highly related to prefrontal cortex ================================================================================ Receptor: ErbB4 ================================================================================ Ligand on the ErbB4: neuregulin ================================================================================ PP2B is activated STEP is activated ================================================================================ NR2A has P ================================================================================ NR2A reduces ================================================================================ The ratio of NR2A and NR2B is important ================================================================================ The ratio switches in 2 periods; development, hippocampus's LTP ================================================================================ ================================================================================ Activity dependent Coincident detector are well implemented in NMDA-R The core concept in terms of NMDA-R is that the ratio of NR2A/NR2B is important ================================================================================ Invertebrates ================================================================================ Vertebrates ================================================================================ The life is the molecular system which performs "Darwin evolution" which is in other words "activity dependent" ================================================================================ Ribosome mRNA Raw polypeptide Separated ribosome into large and sub units Red square: final form of single protein ================================================================================ ================================================================================ P (which is label for energy) is attached to protein by kinase P (which is label for energy) is detached from protein by phosphate ================================================================================