| |
Name | Pathway Name /
Pathway No. | Accession
Type | Initial
Conc.
(uM) | Volume
(fL) | Buffered | Sum Total Of |
| 1 | ATP | AC
Pathway No. 85 | Network | 5000 | 1000 | Yes | - |
| | ATP is present in all cells between 2 and 10 mM. See Lehninger. |
| 2 | Ca-ext | CaRegulation
Pathway No. 86 | Network | 4000 | 100000 | Yes | - |
| | Extracell Ca conc = 4 mM Extracell vol assumed 100 X cell vol It is kept buffered anyway for the puroposes of the model, so the concentration won't change. |
| 3 | CaMKII | CaMKII
Pathway No. 80 | Network | 70 | 1000 | No | - |
| | Huge concentration of CaMKII. In PSD it is 20-40% of protein, so we assume it is around 2.5% of protein in spine as a whole. This level is so high it is unlikely to matter much if we are off a bit. This comes to about 70 uM. Seen the review: Hanson and Schulman 1992 Ann. Rev. Biuochem 60:559-601 |
| 4 | total-CaMKII | CaMKII
Pathway No. 80 | Network | 70 | 1000 | Yes | - |
| | This pool is purely here to provide a single, fixed number, which is the total amount of CaMKII. This is used by the autophosphorylation steps to scale down the rates so that the autophosphorylation reactions are independent of CaMKII levels. |
| 5 | APC | PLA2
Pathway No. 72 | Network | 30 | 1000 | Yes | - |
| | arachodonylphosphatidylcholine is the favoured substrate from Wijkander and Sundler, JBC 202 pp 873-880, 1991. Their assay used 30 uM substrate, which is what the kinetics in this model are based on. For the later model we should locate a more realistic value for APC. For now it is treated as a buffered metabolite. |
| 6 | CaM | CaM
Pathway No. 81 | Network | 20 | 1000 | No | - |
| | There is a LOT of this in the cell: upto 1% of total protein mass. (Alberts et al, Mol Biol. of the Cell, Garland Publishers) Say 25 uM. Meyer et al Science 256 1199-1202 1992 refer to studies saying it is comparable to CaMK levels. |
| 7 | neurogranin | CaM
Pathway No. 81 | Network | 10 | 1000 | No | - |
| | Also known as RC3 and p17 and BICKS. Concentration in brain >> 2 uM from Martzen and Slemmon J Neurosci 64 92-100 1995. Concentration in dend spines is much higher than overall, so it could be anywhere from 2 uM to 50. We will estimate 10 uM as a starting point. Gerendasy et al JBC 269:35 22420-22426 1994 have a skeleton model (no numbers) indicating CaM-Ca(n) binding. |
| 8 | AMP | AC
Pathway No. 85 | Network | 10 | 0.0016667 | Yes | - |
| | AMP is a tightly regulated metabolite, so here we simply buffer it to its resting value. The value doesn't really matter to any of the calculations since it acts like a one-way sink. |
| 9 | PIP2 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 10 | 1000 | Yes | - | |
| | PIP2 is a bit troublesome in this model. Its level is well below what it should be based on more recent data. This value is kept in this model to correspond to the Km used in the enzymes. A scale factor of 5-10 in both terms would cancel out but improve the parameter estimate. |
| 10 | Ca-sequester | CaRegulation
Pathway No. 86 | Network | 6.3328 | 160 | No | - |
| | This is the sequestered Calcium pool. The vol is 0.16 * the vol of the cell as a whole. This pool should really equilibrate with a highly buffered pool of Calcium, but that is not present in this version of the model. |
| 11 | temp-PIP2 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 2.5 | 1000 | Yes | - | |
| | This is a steady PIP2 input to PLA2. The sensitivity of PLA2 to PIP2 discussed below does not match with the reported free levels which are used by the phosphlipase Cs. My understanding is that there may be different pools of PIP2 available for stimulating PLA2 as opposed to being substrates for PLCs. For that reason I have given this PIP2 pool a separate identity. As it is a steady input this is not a problem in this model. Majerus et al Cell 37:701-703 report a brain concentration of 0.1 - 0.2 mole % Majerus et al Science 234:1519-1526 report a huge range of concentrations: from 1 to 10% of PI content, which is in turn 2-8% of cell lipid. This gives 2e-4 to 8e-3 of cell lipid. In concentrations in total volume of cell (a somewhat strange number given the compartmental considerations) this comes to anywhere from 4 uM to 200 uM. PLA2 is stim 7x by PIP2 (Leslie and Channon BBA 1045:261(1990) Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs, so I'll use a value at the lower end of the scale for basal PIP2. |
| 12 | PDE1 | AC
Pathway No. 85 | Network | 2 | 1000 | No | - |
| | CaM-Dependent PDE. 66KDa Borisy et al J Neurosci 12(3):915-923 About 0.6% of membrane protein. so estimate 2 uM as conc in brain. Also see Conti et al Adv Sec Mess Phosphoprotein Res 1992 25:87-99 |
| 13 | PP1-active | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 1.8 | 1000 | No | - | |
| | Cohen et al Meth Enz 159 390-408 is main source of info concentration of enzyme = 1.8 uM |
| 14 | I1 | PP1
Pathway No. 82 | Network | 1.8 | 1000 | No | - |
| | I1 is a 'mixed' inhibitor, but at high enz concs it looks like a non-compet inhibitor (Foulkes et al Eur J Biochem 132 309-313 9183). We treat it as non-competitive, so it just turns the enzyme off without interacting with the binding site. Cohen et al 1989 Ann rev Biochem 58:453-508 refer to results where concentration of the inhibitor is 1.5 to 1.8 uM. In order to get complete inhib of PP1, which is at 1.8 uM, we need >= 1.8 uM. |
| 15 | PKC-cytosolic | PKC
Pathway No. 71 | Network | 1 | 1000 | No | - |
| | Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells Kikkawa et al 1982 JBC 257(22):13341 have PKC levels in brain at about 1 uM. The cytosolic form is the inactive PKC. This is really a composite of three isoforms: alpha, beta and gamma which have slightly different properties and respond to different combinations of Ca, AA and DAG. |
| 16 | G-GDP | Gq
Pathway No. 74 | Network | 1 | 1000 | No | - |
| | This is the G-alpha-beta-gamma trimer in association with GDP. From Pang and Sternweis JBC 265:30 18707-12 1990 we get concentration estimate of 1.6 uM to 0.8 uM. I use 1 uM which is well within this range. |
| 17 | Grb2 | Sos
Pathway No. 78 | Network | 1 | 1000 | No | - |
| | There is probably a lot of it in the cell: it is also known as Ash (abundant src homology protein). Also Waters et al JBC 271:30 18224 1996 say that only a small fraction of cellular Grb is precipitated out when SoS is precipitated. As most of the Sos seems to be associated with Grb2, it would seem like there is a lot of the latter. Say 1 uM. This would comfortably saturate the SoS. |
| 18 | CaNAB | PP2B
Pathway No. 83 | Network | 1 | 1000 | No | - |
| | Calcineurin A and B subunits. We assume that the A and B subunits of PP2B are always bound under physiological conditions. Tallant and Cheung '83 Biochem 22 3630-3635 have conc in many species, average for mammalian brain is around 1 uM. |
| 19 | PLC_g | PLC_g
Pathway No. 79 | Network | 0.82 | 1000 | No | - |
| | Amount from Homma et al JBC 263:14 6592-6598 1988. Source is rat brain. |
| 20 | PLC | PLCbeta
Pathway No. 73 | Network | 0.8 | 1000 | No | - |
| | Total PLC = 0.8 uM see Ryu et al JBC 262 (26) pp 12511 1987 |
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