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Connexons and pannexons: newcomers in neurophysiology.

Cheung G, Chever O, Rouach N - Front Cell Neurosci (2014)

Bottom Line: In order to fully understand the dynamic properties and roles of connexin hemichannels and pannexons in the brain, it is essential to decipher whether they also have some physiological functions and contribute to normal cerebral processes.Here, we present recent studies in the CNS suggesting emerging physiological functions of connexin hemichannels and pannexons in normal neuronal activity and behavior.We also discuss how these pioneer studies pave the way for future research to extend the physiological relevance of connexons and pannexons, and some fundamental issues yet to be addressed.

View Article: PubMed Central - PubMed

Affiliation: Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University Paris, France.

ABSTRACT
Connexin hemichannels are single membrane channels which have been traditionally thought to work in pairs to form gap junction channels across two opposing cells. In astrocytes, gap junction channels allow direct intercellular communication and greatly facilitate the transmission of signals. Recently, there has been growing evidence demonstrating that connexin hemichannels, as well as pannexin channels, on their own are open in various conditions. They allow bidirectional flow of ions and signaling molecules and act as release sites for transmitters like ATP and glutamate into the extracellular space. While much attention has focused on the function of connexin hemichannels and pannexons during pathological situations like epilepsy, inflammation, neurodegeneration or ischemia, their potential roles in physiology is often ignored. In order to fully understand the dynamic properties and roles of connexin hemichannels and pannexons in the brain, it is essential to decipher whether they also have some physiological functions and contribute to normal cerebral processes. Here, we present recent studies in the CNS suggesting emerging physiological functions of connexin hemichannels and pannexons in normal neuronal activity and behavior. We also discuss how these pioneer studies pave the way for future research to extend the physiological relevance of connexons and pannexons, and some fundamental issues yet to be addressed.

No MeSH data available.


Related in: MedlinePlus

Panx1 channels modulate neuronal excitability, synaptic transmission and plasticity in hippocampal slices. (A,B) Metabolic autocrine regulation of neuronal activity via Panx1 channels and adenosine. (A) Sample trace showing increased outward current upon reduced extracellular glucose (from 11 to 3 mM) and subsequent reversal to baseline with 10panx application (100 μM) in CA3 pyramidal neurons. Bar graphs showing the reversal of reduced glucose-induced outward current amplitude with 10panx (left), and that pretreatment with 10panx prevented reduced glucose-induced outward current. **p < 0.01. (B) Schematic showing a proposed model of purinergic autocrine regulation in CA3 pyramidal neurons. When [ATP]i is sufficient (1), low [Glucose]e (2) induces ATP release from Panx1 channels on neurons (3). ATP is then dephosphorylated to adenosine (4) which activates adenosice A1R rceptors (5). KATP channels are then opened leading to a decrease in neuronal excitability. (C–F) Panx1 regulates synaptic transmission, LTP and LTD. (C) Input-Output curves showing increased synaptic transmission in Panx1−/− (black line) compared to control Panx1+/+ (dashed line) mice. Such effect was abolished in Panx1−/− slices treated with 3 μM adenosine (red line). *p < 0.01; **p < 0.001. (D) LTP evoked by high frequency stimulation (four trains of 10 shocks at 100 Hz every 1 s; HFS) is enhanced in Panx1−/− (filled gray) compared to control Panx1+/+ (open gray) mice. Adenosine treatment in Panx1−/− slices (filled red) restores LTP levels to that of untreated control mice. Figure insets illustrate responses before and 30 min post HFS. Scale bar: 0.5 mV, 10 ms. (E) LTP induced by the delivery of theta burst stimulation protocol (TBS) is increased in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young mice (+/+, gray; −/−, blue). In the presence of 100 μM probenecid (Panx1 channel blocker; red), only transient LTP was enhanced. (F) Similarly, LTD induced by paired-pulse low frequency stimulation protocol (1Hz for 15 min; PP-LFS) are impaired in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young equivalent (+/+, gray; −/−, blue). In the presence of 100 μM probenecid, only a transient LTD was observed. Adapted, with permission, from Kawamura et al. (2010) (A,B), Prochnow et al. (2012) (C,D) and Ardiles et al. (2014) (E,F).
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Figure 2: Panx1 channels modulate neuronal excitability, synaptic transmission and plasticity in hippocampal slices. (A,B) Metabolic autocrine regulation of neuronal activity via Panx1 channels and adenosine. (A) Sample trace showing increased outward current upon reduced extracellular glucose (from 11 to 3 mM) and subsequent reversal to baseline with 10panx application (100 μM) in CA3 pyramidal neurons. Bar graphs showing the reversal of reduced glucose-induced outward current amplitude with 10panx (left), and that pretreatment with 10panx prevented reduced glucose-induced outward current. **p < 0.01. (B) Schematic showing a proposed model of purinergic autocrine regulation in CA3 pyramidal neurons. When [ATP]i is sufficient (1), low [Glucose]e (2) induces ATP release from Panx1 channels on neurons (3). ATP is then dephosphorylated to adenosine (4) which activates adenosice A1R rceptors (5). KATP channels are then opened leading to a decrease in neuronal excitability. (C–F) Panx1 regulates synaptic transmission, LTP and LTD. (C) Input-Output curves showing increased synaptic transmission in Panx1−/− (black line) compared to control Panx1+/+ (dashed line) mice. Such effect was abolished in Panx1−/− slices treated with 3 μM adenosine (red line). *p < 0.01; **p < 0.001. (D) LTP evoked by high frequency stimulation (four trains of 10 shocks at 100 Hz every 1 s; HFS) is enhanced in Panx1−/− (filled gray) compared to control Panx1+/+ (open gray) mice. Adenosine treatment in Panx1−/− slices (filled red) restores LTP levels to that of untreated control mice. Figure insets illustrate responses before and 30 min post HFS. Scale bar: 0.5 mV, 10 ms. (E) LTP induced by the delivery of theta burst stimulation protocol (TBS) is increased in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young mice (+/+, gray; −/−, blue). In the presence of 100 μM probenecid (Panx1 channel blocker; red), only transient LTP was enhanced. (F) Similarly, LTD induced by paired-pulse low frequency stimulation protocol (1Hz for 15 min; PP-LFS) are impaired in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young equivalent (+/+, gray; −/−, blue). In the presence of 100 μM probenecid, only a transient LTD was observed. Adapted, with permission, from Kawamura et al. (2010) (A,B), Prochnow et al. (2012) (C,D) and Ardiles et al. (2014) (E,F).

Mentions: ATP-mediated modulations of neurotransmission are not only restricted to astroglial Cx43 HCs. Indeed, an interesting link between Panx channels, which also release ATP, and basal neuronal excitability was reported (Kawamura et al., 2010). Using whole-cell patch clamp recordings, it was demonstrated that changes in extracellular glucose concentration from 11 to 3 mM opened Panx1 channels on rat hippocampal CA3 pyramidal neurons through which ATP is released. Its metabolite adenosine then activates adenosine A1 receptors, leading to the opening of ATP-sensitive K+ channels. As a result of this autocrine regulation, neuronal hyperpolarization occurs, downregulating neuronal activity. The involvement of Panx1 channels was confirmed using CBX, octanol and the selective peptide blocker 10panx (Figures 2A,B). Of note, although decreasing glucose concentration to 3 mM was confirmed to be non-pathological using extracellular recordings, an initial concentration of 11 mM is almost four-fold higher than extracellular glucose concentration in brain tissues in vivo (Shram et al., 1997). Whether this initial hyperglycemic condition contributed to the Panx1-mediated regulation of neuronal activity thus remains to be clarified.


Connexons and pannexons: newcomers in neurophysiology.

Cheung G, Chever O, Rouach N - Front Cell Neurosci (2014)

Panx1 channels modulate neuronal excitability, synaptic transmission and plasticity in hippocampal slices. (A,B) Metabolic autocrine regulation of neuronal activity via Panx1 channels and adenosine. (A) Sample trace showing increased outward current upon reduced extracellular glucose (from 11 to 3 mM) and subsequent reversal to baseline with 10panx application (100 μM) in CA3 pyramidal neurons. Bar graphs showing the reversal of reduced glucose-induced outward current amplitude with 10panx (left), and that pretreatment with 10panx prevented reduced glucose-induced outward current. **p < 0.01. (B) Schematic showing a proposed model of purinergic autocrine regulation in CA3 pyramidal neurons. When [ATP]i is sufficient (1), low [Glucose]e (2) induces ATP release from Panx1 channels on neurons (3). ATP is then dephosphorylated to adenosine (4) which activates adenosice A1R rceptors (5). KATP channels are then opened leading to a decrease in neuronal excitability. (C–F) Panx1 regulates synaptic transmission, LTP and LTD. (C) Input-Output curves showing increased synaptic transmission in Panx1−/− (black line) compared to control Panx1+/+ (dashed line) mice. Such effect was abolished in Panx1−/− slices treated with 3 μM adenosine (red line). *p < 0.01; **p < 0.001. (D) LTP evoked by high frequency stimulation (four trains of 10 shocks at 100 Hz every 1 s; HFS) is enhanced in Panx1−/− (filled gray) compared to control Panx1+/+ (open gray) mice. Adenosine treatment in Panx1−/− slices (filled red) restores LTP levels to that of untreated control mice. Figure insets illustrate responses before and 30 min post HFS. Scale bar: 0.5 mV, 10 ms. (E) LTP induced by the delivery of theta burst stimulation protocol (TBS) is increased in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young mice (+/+, gray; −/−, blue). In the presence of 100 μM probenecid (Panx1 channel blocker; red), only transient LTP was enhanced. (F) Similarly, LTD induced by paired-pulse low frequency stimulation protocol (1Hz for 15 min; PP-LFS) are impaired in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young equivalent (+/+, gray; −/−, blue). In the presence of 100 μM probenecid, only a transient LTD was observed. Adapted, with permission, from Kawamura et al. (2010) (A,B), Prochnow et al. (2012) (C,D) and Ardiles et al. (2014) (E,F).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Panx1 channels modulate neuronal excitability, synaptic transmission and plasticity in hippocampal slices. (A,B) Metabolic autocrine regulation of neuronal activity via Panx1 channels and adenosine. (A) Sample trace showing increased outward current upon reduced extracellular glucose (from 11 to 3 mM) and subsequent reversal to baseline with 10panx application (100 μM) in CA3 pyramidal neurons. Bar graphs showing the reversal of reduced glucose-induced outward current amplitude with 10panx (left), and that pretreatment with 10panx prevented reduced glucose-induced outward current. **p < 0.01. (B) Schematic showing a proposed model of purinergic autocrine regulation in CA3 pyramidal neurons. When [ATP]i is sufficient (1), low [Glucose]e (2) induces ATP release from Panx1 channels on neurons (3). ATP is then dephosphorylated to adenosine (4) which activates adenosice A1R rceptors (5). KATP channels are then opened leading to a decrease in neuronal excitability. (C–F) Panx1 regulates synaptic transmission, LTP and LTD. (C) Input-Output curves showing increased synaptic transmission in Panx1−/− (black line) compared to control Panx1+/+ (dashed line) mice. Such effect was abolished in Panx1−/− slices treated with 3 μM adenosine (red line). *p < 0.01; **p < 0.001. (D) LTP evoked by high frequency stimulation (four trains of 10 shocks at 100 Hz every 1 s; HFS) is enhanced in Panx1−/− (filled gray) compared to control Panx1+/+ (open gray) mice. Adenosine treatment in Panx1−/− slices (filled red) restores LTP levels to that of untreated control mice. Figure insets illustrate responses before and 30 min post HFS. Scale bar: 0.5 mV, 10 ms. (E) LTP induced by the delivery of theta burst stimulation protocol (TBS) is increased in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young mice (+/+, gray; −/−, blue). In the presence of 100 μM probenecid (Panx1 channel blocker; red), only transient LTP was enhanced. (F) Similarly, LTD induced by paired-pulse low frequency stimulation protocol (1Hz for 15 min; PP-LFS) are impaired in adult Panx1−/− (green) compared to Panx1+/+ (black) mice, whereas no difference was observed between young equivalent (+/+, gray; −/−, blue). In the presence of 100 μM probenecid, only a transient LTD was observed. Adapted, with permission, from Kawamura et al. (2010) (A,B), Prochnow et al. (2012) (C,D) and Ardiles et al. (2014) (E,F).
Mentions: ATP-mediated modulations of neurotransmission are not only restricted to astroglial Cx43 HCs. Indeed, an interesting link between Panx channels, which also release ATP, and basal neuronal excitability was reported (Kawamura et al., 2010). Using whole-cell patch clamp recordings, it was demonstrated that changes in extracellular glucose concentration from 11 to 3 mM opened Panx1 channels on rat hippocampal CA3 pyramidal neurons through which ATP is released. Its metabolite adenosine then activates adenosine A1 receptors, leading to the opening of ATP-sensitive K+ channels. As a result of this autocrine regulation, neuronal hyperpolarization occurs, downregulating neuronal activity. The involvement of Panx1 channels was confirmed using CBX, octanol and the selective peptide blocker 10panx (Figures 2A,B). Of note, although decreasing glucose concentration to 3 mM was confirmed to be non-pathological using extracellular recordings, an initial concentration of 11 mM is almost four-fold higher than extracellular glucose concentration in brain tissues in vivo (Shram et al., 1997). Whether this initial hyperglycemic condition contributed to the Panx1-mediated regulation of neuronal activity thus remains to be clarified.

Bottom Line: In order to fully understand the dynamic properties and roles of connexin hemichannels and pannexons in the brain, it is essential to decipher whether they also have some physiological functions and contribute to normal cerebral processes.Here, we present recent studies in the CNS suggesting emerging physiological functions of connexin hemichannels and pannexons in normal neuronal activity and behavior.We also discuss how these pioneer studies pave the way for future research to extend the physiological relevance of connexons and pannexons, and some fundamental issues yet to be addressed.

View Article: PubMed Central - PubMed

Affiliation: Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University Paris, France.

ABSTRACT
Connexin hemichannels are single membrane channels which have been traditionally thought to work in pairs to form gap junction channels across two opposing cells. In astrocytes, gap junction channels allow direct intercellular communication and greatly facilitate the transmission of signals. Recently, there has been growing evidence demonstrating that connexin hemichannels, as well as pannexin channels, on their own are open in various conditions. They allow bidirectional flow of ions and signaling molecules and act as release sites for transmitters like ATP and glutamate into the extracellular space. While much attention has focused on the function of connexin hemichannels and pannexons during pathological situations like epilepsy, inflammation, neurodegeneration or ischemia, their potential roles in physiology is often ignored. In order to fully understand the dynamic properties and roles of connexin hemichannels and pannexons in the brain, it is essential to decipher whether they also have some physiological functions and contribute to normal cerebral processes. Here, we present recent studies in the CNS suggesting emerging physiological functions of connexin hemichannels and pannexons in normal neuronal activity and behavior. We also discuss how these pioneer studies pave the way for future research to extend the physiological relevance of connexons and pannexons, and some fundamental issues yet to be addressed.

No MeSH data available.


Related in: MedlinePlus