Detecting activity-evoked pH changes in human brain

Department of Radiology, University of Iowa, Iowa City, IA 52242, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2012; 109(21):8270-3. DOI: 10.1073/pnas.1205902109
Source: PubMed


Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonance imaging (MRI) strategy, T(1) relaxation in the rotating frame (T(1)ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T(1)ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive (31)P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T(1)ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T(1)ρ was not directly sensitive to blood oxygen content. These observations indicate that localized pH fluctuations occur in the human brain during normal function. Furthermore, they suggest a unique functional imaging strategy based on pH that is independent of traditional functional MRI contrast mechanisms.

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Available from: Brian Dlouhy, May 19, 2014
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    • "nactivation and voltage gating ) as the result of pore mutation and protonation further illustrates the gating role of the outer pore in CNG channels . Changes in pH o can arise in a variety of physio - logical and pathophysiological conditions , such as neuro - nal activity , ischaemia and inflammation ( Kellum et al . 2004 ; Isaev et al . 2008 ; Magnotta et al . 2012 ) . Low pH acts as a negative feedback mechanism that inhibits the CNGA1 channel in a state - dependent manner and may represent an unrecognized endogenous signal regulating CNG physiological functions in diverse tissues ."
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    ABSTRACT: Ion channels control ionic fluxes across biological membranes by residing in any of three functionally distinct states: deactivated (closed), activated (open), or inactivated (closed). Unlike many of their cousin K(+) channels, cyclic nucleotide-gated (CNG) channels do not desensitize or inactivate. Using patch recording techniques, we show that when extracellular pH (pHo) is decreased from 7.4 to 6 or lower, wild-type CNGA1 channels inactivate in a voltage-dependent manner. pHo titration experiments show that at pHo < 7 the current-voltage relations are outwardly rectifying and that inactivation is coupled to current rectification. Single-channel recordings indicate that a fast mechanism of proton blockage underscore current rectification while inactivation arises from conformational changes downstream from protonation. Furthermore, mutagenesis and ionic substitution experiments highlight the role of the selectivity filter in current decline suggesting analogies with the C-type inactivation observed in K(+) channels. The analysis with Markovian models indicates that the non-independent binding of two protons within the transmembrane electrical field explains both the voltage-dependent blockage and the inactivation. Acidic pH by inhibiting the CNGA1 channels in a state-dependent manner may represent an unrecognized endogenous signal regulating CNG physiological functions in diverse tissues. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 12/2014; 593(4). DOI:10.1113/jphysiol.2014.284216 · 5.04 Impact Factor
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    • "However, the functional relevance of ASIC1a in synaptic transmission remains unclear (47,48). Wemmie et al. recently detected local pH changes during normal brain activity in mouse and human brains (9). This study directly supports the potential activation of ASICs during brain activity, although attempts to measure the ASIC-mediated currents during synaptic transmission in hippocampal neurons have not been successful (6,45). "
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    ABSTRACT: Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn(2+), and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel's large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated. [BMB Reports 2013; 46(6): 295-304].
    BMB reports 06/2013; 46(6):295-304. DOI:10.5483/BMBRep.2013.46.6.121 · 2.60 Impact Factor
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    • "How ASICs get activated in physiological conditions remains unclear. However, with functional magnetic resonance imaging, one recent report shows that learning induces acidification in human brain [76]. Although the exact magnitude of pH reduction in this paradigm remains to be determined, this study provides a direct support for potential ASIC activation by protons in physiological conditions. "
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    ABSTRACT: Extracellular acidification occurs in the brain with elevated neural activity, increased metabolism, and neuronal injury. This reduction in pH can have profound effects on brain function because pH regulates essentially every single biochemical reaction. Therefore, it is not surprising to see that Nature evolves a family of proteins, the acid-sensing ion channels (ASICs), to sense extracellular pH reduction. ASICs are proton-gated cation channels that are mainly expressed in the nervous system. In recent years, a growing body of literature has shown that acidosis, through activating ASICs, contributes to multiple diseases, including ischemia, multiple sclerosis, and seizures. In addition, ASICs play a key role in fear and anxiety related psychiatric disorders. Several recent reviews have summarized the importance and therapeutic potential of ASICs in neurological diseases, as well as the structure-function relationship of ASICs. However, there is little focused coverage on either the basic biology of ASICs or their contribution to neural plasticity. This review will center on these topics, with an emphasis on the synaptic role of ASICs and molecular mechanisms regulating the spatial distribution and function of these ion channels.
    Molecular Brain 01/2013; 6(1):1. DOI:10.1186/1756-6606-6-1 · 4.90 Impact Factor
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