BilZ0r
Bluelight Crew
- Joined
- Dec 15, 2003
- Messages
- 6,675
I've reviewed the theories on the mechanism of amphetamine mediated release before. I just thought I'd point out a few more things.
A fact that amazed people when I gave a seminar on the theories at my department, was that all substrates of the monoamine transporter cause release, even the native monoamines.
Now I'm not really sure if I buy the PKC mediated reversal of transporter which I have outlined before, but I'm really quite confident that the mere act of uptake my the transporter gaurantes release. The substrate does not have to do anything more. Now whether the transporter cycle causes Ca2+ build up and this activates PKC which casues the transporter to reverse, or whether its because transporters act as dimers, which transport in opposing directions (which I don't buy, outlined here), or whether this is some transporter-SNARE/syntaxin 1a interaction (Quick et al., unpublished, as cited by 5-HT2), I don't know.
I don't like the first option (PKC) because PKC inhibitors infused into the Striatum (DAT rich) did not reduce amphetamine mediated Dopamine release (1).
I just don't trust the dimer option, but I haven't quite figured out why.
The third one doesn't fit, because I feel amphetamine mediated release should be the same throughout all of the transporters, and NET mediated release still happens when SNAREs are cleved by bottulinum toxin.
Another reason why I don't trust the third is because of this figure
* There is this paper which seems to show that uptake affinity and actual transport are unrelated, that is SERT Ki does not correlate even slightly with uptake Vmax... but the same paper shows a nice correlation between SERT Ki and SERT mediated currents, now I though the currents were dependent on transport, so I don't really know
A fact that amazed people when I gave a seminar on the theories at my department, was that all substrates of the monoamine transporter cause release, even the native monoamines.
Now I'm not really sure if I buy the PKC mediated reversal of transporter which I have outlined before, but I'm really quite confident that the mere act of uptake my the transporter gaurantes release. The substrate does not have to do anything more. Now whether the transporter cycle causes Ca2+ build up and this activates PKC which casues the transporter to reverse, or whether its because transporters act as dimers, which transport in opposing directions (which I don't buy, outlined here), or whether this is some transporter-SNARE/syntaxin 1a interaction (Quick et al., unpublished, as cited by 5-HT2), I don't know.
I don't like the first option (PKC) because PKC inhibitors infused into the Striatum (DAT rich) did not reduce amphetamine mediated Dopamine release (1).
I just don't trust the dimer option, but I haven't quite figured out why.
The third one doesn't fit, because I feel amphetamine mediated release should be the same throughout all of the transporters, and NET mediated release still happens when SNAREs are cleved by bottulinum toxin.
Another reason why I don't trust the third is because of this figure
This shows that over about 15 mixed transporter substrates, over the three monoamine transporters, there is a consistant relationship between uptake inhibition (and hence affinity for the transporter, and presumabley transport as a substrate*) and between release... hence uptake correaltes with release, consistantly.
* There is this paper which seems to show that uptake affinity and actual transport are unrelated, that is SERT Ki does not correlate even slightly with uptake Vmax... but the same paper shows a nice correlation between SERT Ki and SERT mediated currents, now I though the currents were dependent on transport, so I don't really know