EFTA00611569.pdf

FEBS Leans 587 (2013) 1923-1928 ELSEVIER journal homepage: www.FEBSLetters.org Review Minireview: pH and synaptic transmission (ID CrossMarlc Anne Sinning'''. Christian A. Hubner' 'Institute of Human Genetics, University HospitalJena Thechich Schiller University Jena, Kollegiengasse la 0-07743 Jena. Germany °Institute of Physiology and Pathophysiology, Ltniversary Medical Center of the Johannes Gutenberg University, Duesbergweg G 0-55128 Mainz Germany ARTICLE INFO ABSTRACT Article history: Asa general rule a rise in pH increases neuronal activity, whereas it is dampened by a fall of pH. Neu- Received IS April 2013 ronal activity per se also challenges pH homeostasis by the increase of metabolic acid equivalents. Revised 26 April 2013 Moreover, the negative membrane potential of neurons promotes the intracellular accumulation Accepted 26 April 2013 of protons. Synaptic key players such as glutamate receptors or voltage-gated calcium channels Available online 10 May 2013 show strong pH dependence and effects of pH gradients on synaptic processes are well known. How- Edited by Alexander Cabibov. Vladimir ever. the processes and mechanisms that allow controlling the pH in synaptic structures and how Skulachev, Felix Wieland and Wilhelm Just these mechanisms contribute to normal synaptic function arc only beginning to be resolved. 02013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: pH regulation Ion transporter Mouse model Carbonic anhydrase Synaptic transmission CAM Neuronal excitability 1. Introduction pH regulation in intracellular synaptic compartments so far have only been obtained for motor endplates because of their signifi- The strong acidification of synaptic vesicles by the vacuolar - cantly larger dimensions compared to central synapses [4.181. ATPase. which energizes the neurotransmitter loading of synaptic Zhang et al. used the pH-sensitive properties of the yellow fluores- vesicles [11, is a main reason for the large fluctuations in synaptic cent protein to analyse the presynaptic pH in mouse motor end- pH. Synaptic vesicle exocytosis results in the release of protons plates. This study not only supports the importance of into the synaptic cleft as well as in the incorporation of the vacu- presynaptic pH regulators but further provided evidence that the olar H'-ATPase into the presynaptic membrane. Thus synaptic release of vesicles in the peripheral nervous system is accompanied transmission causes a relatively short but strong acidification of by a transient intracellular acidification. Here, the increase in pH the synaptic cleft [2-4]. The extracellular acidosis is subsequently was mainly caused by the activation of plasma membrane Ca2*/ followed by a long, yet transient increase in extrasynaptic pH 151. H'-ATPase and was followed by an unexpected, longer lasting alka- In the hippocampus this alkaline transient can be detected within linisation is due to the transient incorporation of the vacuolar Fr- milliseconds 16.71 and reaches magnitudes as large as 0.1-0.2 pH ATPase into the presynaptic membrane 141. Focal injections of units 181. Mechanisms underlying this rise in pH are not fully BCECF-AM in combination with slice imaging as used for measur- understood but most likely presynaptic Ca2'1H'-ATPase 19.101 ing calcium transients in small synaptic compartments with the extracellular carbonic anhydrases [8]. and GABAA-receptor calcium-sensitive dye Fura [19]. genetically encoded pH indicators mediated bicarbonate efflux [111 are involved. Increased 1181. which also allow ratiometric imaging 120.211. may help to synaptic/neuronal activity can also cause a prolonged extracellular establish adequate and fast pH measurement in small compart- acidification because of the increased cell metabolism [5.12.13]. ments like central pre- and postsynaptic terminals in the future. Although several studies have successfully monitored neuronal Despite these technical limitations the occurrence of rather pH shifts in the brain 12.14.151. only very little is known about pH large, spatially and timely limited. pH fluctuations in the different transients in neuronal microdomains because of technical limita- synaptic compartments is generally accepted and clearly implies dons 116.171. Direct experimental data on pH fluctuations and that pH regulatory elements are essential to maintain proper syn- aptic function. Since many synaptic elements are strongly pH * Corresponding author. dependent, limitations and alterations in synaptic pH homeostasis E-mall address: christian.huebneremtiuni-Jenade (CA. Wilmer). could potentially feed-back on neuronal activity itself. Intriguingly. 0014-5793/136.00 0 2013 Federation of European Biodiemical Societies. Published by Elsevier B.V. All rights reserved. http://dx.dolorgf10.1016b.febslet.2013.04.04S EFTA00611569 1924 A. Sinning CA. HOWier/ FESS Letters 587 (2013) 1923-1928 it has already been shown that direct release of protons during GABA response 147-491. GABAA receptors also conduct bicarbon- vesicle exocytosis can act as a negative feedback on closely associ- ate. As a consequence, GABAergic transmission can cause altera- ated calcium channels in the mammalian retina 13221. In this sys- tions of both intra- and extracellular pH 1111. In contrast to the tem. synaptic cleft acidification of retinal cells is thought to direction of chloride fluxes, which can vary in dependence of the underlie surround inhibition and thereby helps to form the recep- existing chloride gradients, which are set by the cation-chloride tive field (for review see 1231). The discovery of acid-sensing ion co-transporters NKCC1 and KCC2 150-521. the existing gradients channels (ASICs) is another example for a pH-induced feedback always drive HCCIi out of the neurons under physiological condi- mechanisms 1241. At least four genes and their alternatively spliced tions. Both gradients contribute to the balance between neuronal transcripts code for subunits of such ion channels, which belong to excitation and inhibition. Only little is known about the role of the degenerinfepithelial Na' channel superfamily and are character- pH for signaling via GABA8 receptors or receptors of other ized by a strong H'-sensitivity as well as their permeability for cat- neurotransmitters. ions. ASICs are widely expressed in the mammalian nervous system In conclusion, electrical stimulation or synchronized neuronal and have been shown to localize mostly to somato-dendritic regions activity results first in an initial transient alkaline shift of the extra- of neurons 125261. ASICs have been implicated in many neurologi- cellular pH that is followed by a prolonged acidosis (for review see cal disorders like e.g., ischemic stroke, epileptic seizures and pain 151). The short-lived initial increase in pH has been shown to be (for review see1271). Interestingly, one study suggested that seizure sufficient to augment glutamatergic excitation by activation of termination critically depends on ASIC activation by the fall in NMDA receptors in acute slice experiments 1451 and most likely extracellular pH in response to epileptic neuronal activity [281. inhibits GABAergic transmission. In contrast, under conditions of sustained stimulation [531 or pathological neuronal activity (121, 2. Effects of pH transients on presynaptic function the following long-lasting acidosis is predicted to diminish gluta- matergic neurotransmission and boost GABAergic Loading of synaptic vesicles with different neurotransmitters which was confirmed for cultured neurons [541. depends on vesicular proton gradients 1291. Hence, variations in This indicates that intrinsic pH transients serve as a feedback intracellular pH could directly interfere with neurotransmitter mechanism to keep the delicate balance between neuronal excit- loading. It has been shown that the glutamate uptake by astrocytes ability and inhibition but also implies that neuronal and especially is pH sensitive and provides a mechanism which can protect neu- synaptic p11 has to be tightly controlled. rons from glutamatergic excitotoxicity due to reversed glutamate uptake under ischemic conditions 1301. 4. Mechanisms to regulate synaptic pH The function of proteins, enzymatic activity as well as protein- protein interactions are sensitive to alterations in pH and thus In general, cellular pH homeostasis is established by transport changes in pH can impact on the release of synaptic vesicles. which or buffering of acid equivalents. In neurons acid loading is largely depends on the conceited action ofa complex machinery ofdifferent established by Na' independent CI- /HCO3 exchangers [551. proteins (for review see1311).In particular, the initial rise in the pre- whereas Nalt exchangers [561. NC-driven CI' /HCCI; exchangers synaptic calcium concentration mediated via voltage-gated calcium and Na'/HCO3 co-transporters [571 mediate acid extrusion. An- channels 1321 is pH dependent, as the opening and the conductivity other family of bicarbonate transporters, which can be distin- of presynaptic voltage-gated calcium channels strongly depend on guished from the family of SLC4 transporters 155.581, are both extracellular and intracellular pH 1331. Protons can directly classified as members of the SLC26 family [591. however, if at all. bind to sensors within the pore of the channel and thereby reduce members of the SLC26 family of bicarbonate transporters are channel conductance [34.351. shield membrane-bound charges thought to play a minor role for neuronal pH homeostasis 1601. and thus shift the channel activation voltage to more positive values Neuronal pH is also affected by monocarboxylate transporters 136,371. The rise in presynaptic calcium is augmented by release of 1611 but their role in the brain under physiological conditions is calcium from intracellular stores which is mediated via inositol limited whereas they are more important in tissues with a high en- 1.4.5-trisphosphate and ryanodine receptors. Both receptors also ergy demand like in tumors 1621. Although so far no conclusive show strong pH dependence138.391. Studies on spontaneous vesicle data exist that the plasma membrane calcium ATPase also plays release by electrophysiological methods confirmed that lowering of a direct role for pH regulation, a brain-specific isoform with a pre- intracellular pH in hippocampal neurons indeed results in a de- dominant synaptic localization has been described [631, which may ceased rate ofsynaptic vesicle release and hence limited excitability contribute to synaptic pH homeostasis 19,101. 140,411. Further studies are necessary to investigate if presynaptic Bicarbonate is a very important pH buffering system because it pH modulates synapse function mainly by alterations in calcium can be regulated by respiration. Carbonic anhydrases promote the transients or if multiple effects add up. interconversion of carbon dioxide and water to bicarbonate and protons, and thereby significantly contribute to the intra- and 3. Effects of pH transients on postsynaptic function extracellular buffering capacity in the brain 1641. For a more general comprehensive review on cellular pH sen- NMDA receptors are strongly modulated by changes in extracel- sors and regulators, see 1651,151 and 1661. In the following we will lular pH 142,431. An increase in extracellular pH facilitates the acti- mainly focus on the NalH' exchanger NHE1. the Na coupled an- vation of NMDA receptors, whereas a decrease in extracellular pH ion-exchangers NCBE and NDCBE, and NC-HCO3* co-transporters. inhibits ion channel function 142-441. The transient increase in all mediating acid extrusion. extracellular pH elicited by high-frequency stimulation of afferents in the hippocampus has been shown to be sufficient to augment NMDA-receptor responses in vitro 1451. This is most likely also 5. NHE1 relevant in vivo both in physiological and pathophysiological conditions. In contrast, kinetics and amplitudes of AMPA- and The transmembrane NC-gradient is established by the Na1K' Kainate-receptors are only marginally modulated by alteration of ATPase. The Na' gradient is then used to energize the electroneu- extracellular pH 1461. tral exchange of one extracellular sodium for one proton by Nal Interestingly, GABAA receptor mediated currents are enlarged H' exchangers (NHE) 1671. So far 9 different isoforms of Halle by low extracellular pH. whereas a high pH rather inhibits the exchangers have been identified and all of these are expressed in EFTA00611570  A. Slum& CA HatinerIFEBS Letters S87(2013) i92 s "i_., 192S the central nervous system (for review see [681). NHE1iSLC9A1 is Wildtype Synaptosome ubiquitously expressed and a multifunctional protein which does not only contribute to intracellular pH regulation but also volume regulation, cell migration, and also interacts with components of the cytoskeleton [69]. Because of the lack of suitable antibodies localization studies for Slc9a1 are limited. However, most studies suggest that Slc9a1 localizes to presynaptic nerve terminals of GABAergic neurons [54.70.711. Disruption of Slc9a1 in mice re- sulted in a severe phenotype with locomotor deficits, epileptic sei- zures. neurodegeneration, and early mortality [72.73]. Slc9a1 deficient neurons had a lower steady-state pH and a delayed recov- ery from acid loads 1741. The epileptic phenotype in Slc9a1 knock- Slc4a8 out mice is therefore surprising, because an increase in pH is SNAP25 generally associated with an increase of neuronal excitability. However, disruption of Nhel results in a more complex phenotype with increased Na'-current density in hippocampal neurons Fig. 1. Presynaplic expression of SIC4alliNIXIIL Transmission electron microscopy of a freeze-fractured synaptosomes isolated from wild-type mouse brains immu- [75.761 as well as increased neuronal cell death 172]. There is also nogold-labeled for SkOaS (large grains 10 nm) and the presynapuc marker SNAP25 indirect evidence from electrophysiological recordings with phar- (small grains 5 am). Images show the proteoplasmic side of synaptosane mem- macological inhibitors of Na'ffit exchange like amiloride, suggest- branes. Scale bars correspond to 100 and 50 nm ing that the Neill' exchanger, most likely NHE1, localizes to inhibitory and excitatory presynaptic nerve terminals [54.70.71]. In an elegant study by Dietrich and Morad the impact of extracel- was nicely supported by the electrophysiological characterization lular pH buffering on the spontaneous release of GABAergic vesi- of Slc4a8 knockout mice [411 and confirmed in an independent cles in cerebellar granule cells was investigated. The results from study [91]. In agreement with the classification of NDCBE as an this study suggest that Nhel activity may not only affect presynap- acid extruder, Slc4a8 deficient neurons displayed a lower steady tic vesicle release by increasing intracellular pH but also boost state pH and a defective pH regulation. Electrophysiological analy- GABAergic neurotransmission by increasing GABAA receptor re- sis and FM-imaging further showed a decrease in spontaneous and sponses at the postsynapse via the extracellular pH [541. stimulated release of glutamatergic synaptic vesicles in knockout neurons. In accordance with a predominant presynaptic localiza- 6. Na coupled anion-exchangers tion. there was no effect on the post-synaptic kinetics of AMPA receptor currents detected. Moreover, the release of GABAergic From early pH recordings in the squid giant axon and in snail vesicles as evidenced from recordings of mIPSCs in acute hippo- neurons it became evident that NC-dependent Cr/NCO; ex- campal brain slices did not differ between genotypes [411. In con- change plays an essential role in the control of intracellular pH of trast to NDCBE. NCBE has also been detected in hippocampal neurons 177.781. This observation has been supported by the dem- intemeurons and co-localizes with pre- and postsynaptic markers onstration of Na'-driven Cr/NCO; exchange in different prepara- of GABAergic synapses in the hippocampus [891. The recovery of tions of hippocampal neurons [79-82]. But the molecular correlate hippocampal principal cells from add loads was delayed in acute remained unclear, until a first cDNA was cloned from drosophila brain slices of Slc4a10 knockout mice, although there was no dif- [831 and from a mouse insulinoma cell line [84]. In mammals ference in the steady state pH. Here, this affected network excit- Na'-dependent Cl-/HCO; exchange is mediated by NDBCE ability was studied in the 4-aminopyridine model of interictal (SLC4A8) and NCBE (SLC4A10). The initial transport characteriza- discharges in acute brain slices. Although the frequency of the tion of NCBE/SLC4A10 as NC-dependent Cl- /HCO3 exchanger interictal-like events at baseline levels did not differ between was confirmed for rat 184-861. whereas the human cDNA was genotypes, the decreased frequency upon a propionate pulse was rather characterized as an electroneutral /HCO; co-transporter prolonged in the knockout [891. Interestingly, disruption of either (NBCn2) with CI- self-exchange activity 1871. Some of the Slc4a8 or the Slc4a10 in mice increased the seizure threshold in controversy may be explained by the different expression different seizure inducing paradigms [41,89]. In contrast, Slc9a1 systems used in the different studies like mammalian cells and and Slc4a3 knockout mice are more susceptible to seizures [72.94 Xenopus oocytes, temperature and composition of solutions. the transfectionjinjection efficiency or molecular tagging of the 7. Na' /NCO; co-transporters transport proteins. In drosophila disruption of Na'-dependent CI'/HCO3 exchange Na' /HCO; co-transporters also mediate net acid extrusion. The results in early lethality of the larvae [831. Surprisingly, the pheno- electrogenic NI/HCO3 co-transporter Slc4a4 (also called NBCe1) type of Slc4a8 knockout mice is very mild with some minor deficits and the electroneutral Na'/HCCIi co-transporter Slc4a7 (also in different behavioral paradigms [41.881. whereas Slc4a10 knock- called NBCn1) are broadly expressed in the central nervous system out mice experience a critical period within their first week of life [93.94 Slc4a7 was shown to co-localize with PSD-95, a postsynap- with a decreased gain of body weight during postnatal develop- tic protein of glutamatergic synapses [931. Slc4a7 expression was ment. They also display a drastic reduction of brain ventricle size increased upon metabolic acidosis and this up-regulation was [891 and visual impairment 1901. associated with glutamate excitotoxicity [95]. Slc4a7 knockout Details expression analysis in the brain revealed a significant mice have been reported to display severe sensory deficits [961. overlap between both transporters. In the hippocampus Slc4a8 as however, a detailed analysis of its role for synaptic transmission well as Slc4a10 are expressed in pyramidal neurons 1411. The syn- is missing to date. aptic expression of Slc4a8 was further analyzed by ultrastructural Recent data suggest that Slc4a4 helps to prevent the large, pro- analysis [41.911. Transmission electron microscopy of freeze-frac- longed, Ca2"-dependent alkaline shift upon depolarization of neu- tured synaptosomes of wild-type mice revealed that Slc4a8 co- rons 1971. As prolonged positive shifts in membrane potential. localizes with different presynaptic markers like e.g., syntaxin which might cause a sustained net alkaline shift, are a recurrent [411 or SNAP-25 (Fig. 1). The presynaptic expression of Slc4a8 condition during normal brain function, depolarization activated EFTA00611571 1926 A. Sinning CA. Hubner/FEES Letters S87 (2013) 1923-1928 Glutamatergic GABAergic HI Presynapse Slc4a10 NCO; HCO3- Icgel Slc4a301 ? CA P Kos HCO GASA.R Slc4a7 HCOic NMDA-R SkAa10 NCO, Postsynapse Flg. 2. Model displaying different regulators involved in the control of synaptic pH. Sk4a8 localizes to glutamatergic presynapses and modulates the release of glutamate vesicles in a pH-dependent manner (411. Sk9a1 appears to play an important role for pH regulation at GABAergic nerve terminals (691. Sic4a10 is likely to be expressed on both sides of CABAergic synapses 188). Slc4a7 localizes to the postsynaptic site (941. Extracellular and probably also intracellular CM increase the buffering capacity of the different compartments 18). Whether or not 51c4a3 and other pH regulators modulate synaptic activity remains unclear. acid extrusion most likely also plays a role under physiological surprise that several proteins involved in local pH control localize conditions. It was speculated that this depolarization induced alka- to synaptic structures. The use of high resolution microscopy with linization may be an adaptation to preempt untoward acidification better pH sensitive probes may allow measuring the pH in different from large intracellular Ca2' loads, while maintaining or accelerat- synaptic compartments and how the pH changes with synaptic ing the rate of glucose utilization through the glycolytic pathway. activity. These techniques will also help us to address the role of Interestingly, a parallel Cr-dependent mechanism also contrib- the different proteins involved in pH homeostasis more precisely uted to this depolarization induced alkalinization, but its molecu- (Fig. 2). A better understanding of these processes could also help lar correlate is yet unclear 1971. to identify new pharmacological targets to treat epilepsy or patho- logical conditions involving synaptic transmission. 8. Carbonic anhydrases References Carbonic anhydrases (CA) catalyse the rapid interconversion of carbon dioxide and water to bicarbonate and protons and vice ver- 11) Forgac, M. (2007) Vacuolar ATPases: rotary proton pumps in physiology and sa. CA activity was first described in red blood cells 1981 and later pathophysiology. Nat. Rev. Mol. Cell Biol. 8, 917-929. 12) Krishtal, 0.. Osipchuk, V.. Shelest. T. and Smimoff. S. (1987) Rapid became evident in many other organs. In the mammalian brain at extracellular pH transients related to synaptic transmission in rat least 10 catalytically active isoforms or CAs have been described. hippocampal slices. Brain Res. 436. 352-356. which differ in cellular 199,1001 and sub-cellular 1101.1021 locali- 13) DeVries. S. (2001) Exocytosed protons feedback to suppress the Ca2' current in mammalian cone photoreceptors. Neuron 32. 1107-1117. zation. Evidence on the role of carbonic anhydrases for synaptic 14) Zhang, Z.. Nguyen. ILT.. Barrett. E.F. and David, G. (2010) vesicular ATPase transmission has largely been deduced from studies with pharma- inserted into the plasma membrane of motor terminals by exocytosis cological blockers of CA. Experiments with membrane-permeant alkalinizes cytosolic pH and facilitates endocytosis. Neuron 68, 1097-1108. Is] Chester, M. (2003) Regulation and modulation of pH in the brain. Physiol. Rev. and membrane-impermeant blockers of carbonic anhydrases re- 83. 1183-1221. vealed that extracellular CA are involved in the regulation of the 161 Gottfried, JA and Chester, M. (1996) Temporal resolution of activity- interstitial pH in the brain 18.1031. The extracellular and mem- dependent pH shifts in rat hippocampal slices. J. 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