Wednesday, February 27, 2013

GABA, how exciting!

I would like to thank my good friend Anonymous for asking me a great question on a previous post.

Anonymous asks:
"Are there any known transmitters in the NS that activate both inhibitory receptor subtypes AND excitatory receptor subtypes? Or does every known transmitter activate EITHER a bunch of excitatory subtypes OR a bunch of inhibitory subtypes?"
 (btw. This doesn't qualify as a LMAYQ post because it's a real true question that someone directly asked, not a search term)

While I don't know of any instances of glutamate (excitatory) activating GABA (inhibitory) receptors or of GABA activating glutamate receptors, there is an interesting little way that GABA can activate an inhibitory receptor, but actually help excite the cell. 

GABA receptor (source)

 Here's how that works: GABA(A) receptors are permeable to chloride ions, and as the picture above shows, chloride ions (Cl-) are negatively charged. When GABA binds to the receptor, the receptor opens and chloride ions rush in, bringing their negative charge with them. This hyperpolarizes the cell, meaning it brings it lower and lower in total charge (membrane potential), which brings it further and further away from the threshold where it will fire an action potential.

BUT.... if there is a lot of chloride inside the cell already (or if the cell is resting more negatively than the chloride reversal potential), chloride will actually flow out of the cell, bringing its negative charge with it. Negative ions flowing out of the cell will depolarize the neuron increasing its total charge (membrane potential), which brings it closer and closer to the threshold where it will fire an action potential.

GABA reversing at -62mV (source)

A paper published last year in the Journal of Neuroscience shows that in a model of a hippocampal neuron, when a strong excitatory (glutamate) stimulation happens right after a GABA stimulation close by on the dendrite, the cell is actually more likely to fire than when the glutamate stimulation occurs on its own. This effect is dependent on the location of the GABA stimulation along the dendrite.

Chiang et al., 2012 Figure 4E (GPSP in the dendrite)

This figure shows that a GABA stimuation (first dotted line, blue trace) can push the glutamate (excitatory) stimulation (second dotted line, red trace) up to the point of firing an action potential (green trace). This paper also showed that GABA can still inhibit the action potential in these cells, it just has to be at the soma and almost the same time as the glutamatergic input.

Chiang et al., 2012 Figure 4G (GPSP in the soma)

 So there you have it, GABA enhancing the likelihood of an action potential and acting excitatory sometimes, and acting inhibitory other times. 

 © TheCellularScale Chiang PH, Wu PY, Kuo TW, Liu YC, Chan CF, Chien TC, Cheng JK, Huang YY, Chiu CD, & Lien CC (2012). GABA is depolarizing in hippocampal dentate granule cells of the adolescent and adult rats. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (1), 62-7 PMID: 22219270


  1. I know it's not really what the question is asking, but in C. elegans we have a totally mismatched system; glutamate and GABA are excitatory or inhibitory depending on the RECEPTOR, not the transmitter itself. So there are plenty of glutamate-gated chloride channels and glutamate-gated calcium channels (leading to inhibition and excitation, respectively).

    That's one reason even though we know the connectivity and we can guess the transmitter that is released, we still have no idea of the sign of almost any of the synapses in the worm nervous system ;)

  2. (Also, I'd point out that you should mention rebound excitation; I know releasing a cell held at a hyperpolarized potential can cause spiking and Izikevich makes a big deal about how depending on the phase of the cycle, inhibitory pulses of current can cause spiking, but I'm not sure how much that happens in vivo.)

  3. Great points! I am certainly rodent-centric in my neuron knowledge, so thanks for pointing to the C. Elegans info.

    As for rebound excitation, doesn't that have to do with the intrinsic channels of the neuron, like the H current? I'll have to look into how that interacts with synaptic inputs.

  4. Hi, it's me again. :)

    Actually, I meant transmitters besides GABA and glutamate. But since asking my question I think I figured out the answer myself. I did some digging and found out that at least one transmitter (ACh) has both excitatory/depolarizing receptor subtypes (nicotinic) and inhibitory/hyperpolarizing receptor subtypes (muscarinic). I don't know how many other transmitters are like this but at least I have my answer that not all neurotransmitters are solely either excitatory or inhibitory in their effects.

    I asked with transmitters besides GABA and glutamate in mind because based on what I've learned I had assumed that GABA and glutamate were always inhibitory and excitatory, respectively. So your post was fascinating insofar as it showed the situation to be a little more complex than that. Thanks for the answer!

  5. Hi Anonymous!
    I see what you mean now, glad you found some information about it. Another neurotransmitter that might do something to both types of receptor is glycine, though I don't know much about it at the moment.
    Thanks for asking an fascinating question!

  6. Hi
    I would be happy to jump out of lurking shadows and contribute if possible. The fact that GABAA Receptors in certain circumstances can mediate cell depolarization and excitation has been observed for a long time
    However it is usually restricted to early postnatal period (that is why the paper you cite got so much attention).
    It may be little offtopic byt suprising idea that glutamate potentiates (but not directly activates) inhibitory anionselective glycine receptors has appeared a few years ago
    Glycine is both full agonist at inhibitory glycine receptors and a coagonist for NMDA receptors (although in physiological setting D-serine is more common coagonist for NMDA receptors).
    Thanks for great blog. Back to lurking.

  7. Thanks for de-lurking Miszcz! And thanks for the informative links! It's great that people who know more about this stuff than me read this blog. Please keep commenting.

  8. Wow! There's a lot here about how GABA stimulates the brain. I now understand the negative correlation between alcohol and GABA; too much relaxation and less inhibition with an increase and GABA reduces brain activity. This really inhibits action potential.