According to the current view, kcc2 expression is strongly upregulated in most brain areas during postnatal development, while nkcc1 expression is downregulated the same time, thus the balance is shifted to kcc2. Kcc2 expression is downregulated by strong neuronal activity and trauma in mature neurons, and mechanisms responsible for this downregulation are studied by several groups all over the world. Kcc2 downregulation is supposed to be a reason for seizures.

Dear Pavel, thanks for your response. I agree with you on the downregulation of KCC2 under traumatic or epileptic conditions. Activity dependent downregulation of KCC2 has been reported, but there seems to be no information on activity dependent regulation of NKCC1. Although, trauma induced downregulation of KCC2 seems to be often accompanied by an upregulation of NKCC1 (Richard Miles et al , Jasper's Basic mechanisms of the epilepsies) and a similar scenario seems to persist under intractable seizure conditions.

Would it be possible that NKCC1 and KCC2 function as opposite sides of the same coin? Downregulation of one automatically causes an upregulation of the other and vice versa?

Dear Deepak, your idea about NKCC1 upregulation may occur to be true. Indeed, in some cases KCC2 and NKCC1 are regulated (expression and function) in opposite directions. In addition to the opposite dynamics of the their expression profiles during development, there is also an opposite mode of the functional regulation for the two cotransporters by SPAK/OSR1 kinases.

Dear Pavel, That sounds very interesting. Could you send me some references?

Thanks!

Dear Deepak,

I would like to add a word of caution. The opposite mode of regulation of KCC2 and NKCC1 by kinases, pointed out by Pavel Uvarov, is just one aspect of a probably more complex regulation of these two key transporters. Conceivably the developmental switches (e.g. release of KCC2 expression from NRSF suppression or reversal of DNA methlyation in case of NKCC1) may be kind of reset. However, in human epileptogenic tissues we find also a decline in bumetanide-sensitive i.e. NKCC1-mediated chloride extrusion. On average NKCC1 is reduced by 60 % but KCC2 decreased by 80%.

(Deisz et al. 2011, J. Physiol).

Best regards

Rudolf