Limits...
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

Cx HCs and Panx1 channels have significant roles in synaptic transmission essential for vision. (A,B) Cx55.5 HCs are important for contrast sensitivity in zebrafish retina. (A) To measure light-induced feedback responses, cones were first saturated with a 20 μm spot of light. A full-field light flash induced an inward current in cones due to negative feedback from horizontal cells. Cx55.5 mutant (red) cones showed a decreased feedback response compared to wild-type (black), as shown in sample traces. (B) Optokinetic gain, as a measure of contrast sensitivity, was determined by dividing the eye movement velocity by the velocity of the stimulus over a range of contrast in zebrafish larvae. This was significantly decreased in mutant compared to wild-type zebrafish. (C–E) Reciprocal regulation between resting microglia and neuronal activity via Panx1 channels. (C) Glutamate uncaging was performed in the intact zebrafish larvae to evoke Ca2+ activities of tectal neurons within 20 μm around the uncaging point of 1 μm in the soma layer of the optic tectum. From the side of microglia facing the uncaging point (“unc”), the proportion of the number of bulbous normalized to all process tips (“Bulbousunc/Tipunc”) is shown for larvae injected with splice morpholino oligonucleotides (MO) 6-min before (clear) and 24-min (gray) and 59-min (black) after uncaging. The increased in bulbous endings is shown in control MO, but abolished in Panx1 expression downregulation MO1 and MO2. (D) Normalized intensities of Ca2+ activities (light response amplitude) of tectal neurons in vivo evoked by moving bars at indicated frequencies are shown. Response is significantly reduced in neurons after microglial contact (red filled vs. clear bars) as compared to non-contact (black filled vs. clear bars). Numbers of neurons examined are shown on bars. (E) Schematic diagram showing a proposed model of microglial modulations of neuronal activity via Panx1 channels. During neuronal activity, neurons secrete “find me” signal locally (ATP being a candidate) via Panx1 channels, which steer microglial processes toward them (from “Surveying” to “I”). Bulbous endings are then formed on these processes promoting contact with neurons (“II”). Upon such contact, neuronal activity is downregulated (“III”). **p < 0.01; ***p < 0.001. Adapted, with permission, from Klaassen et al. (2011) (A,B), Li et al. (2012) (C,D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4219455&req=5

Figure 4: Cx HCs and Panx1 channels have significant roles in synaptic transmission essential for vision. (A,B) Cx55.5 HCs are important for contrast sensitivity in zebrafish retina. (A) To measure light-induced feedback responses, cones were first saturated with a 20 μm spot of light. A full-field light flash induced an inward current in cones due to negative feedback from horizontal cells. Cx55.5 mutant (red) cones showed a decreased feedback response compared to wild-type (black), as shown in sample traces. (B) Optokinetic gain, as a measure of contrast sensitivity, was determined by dividing the eye movement velocity by the velocity of the stimulus over a range of contrast in zebrafish larvae. This was significantly decreased in mutant compared to wild-type zebrafish. (C–E) Reciprocal regulation between resting microglia and neuronal activity via Panx1 channels. (C) Glutamate uncaging was performed in the intact zebrafish larvae to evoke Ca2+ activities of tectal neurons within 20 μm around the uncaging point of 1 μm in the soma layer of the optic tectum. From the side of microglia facing the uncaging point (“unc”), the proportion of the number of bulbous normalized to all process tips (“Bulbousunc/Tipunc”) is shown for larvae injected with splice morpholino oligonucleotides (MO) 6-min before (clear) and 24-min (gray) and 59-min (black) after uncaging. The increased in bulbous endings is shown in control MO, but abolished in Panx1 expression downregulation MO1 and MO2. (D) Normalized intensities of Ca2+ activities (light response amplitude) of tectal neurons in vivo evoked by moving bars at indicated frequencies are shown. Response is significantly reduced in neurons after microglial contact (red filled vs. clear bars) as compared to non-contact (black filled vs. clear bars). Numbers of neurons examined are shown on bars. (E) Schematic diagram showing a proposed model of microglial modulations of neuronal activity via Panx1 channels. During neuronal activity, neurons secrete “find me” signal locally (ATP being a candidate) via Panx1 channels, which steer microglial processes toward them (from “Surveying” to “I”). Bulbous endings are then formed on these processes promoting contact with neurons (“II”). Upon such contact, neuronal activity is downregulated (“III”). **p < 0.01; ***p < 0.001. Adapted, with permission, from Klaassen et al. (2011) (A,B), Li et al. (2012) (C,D).

Mentions: In addition to their contributions to synaptic and higher level brain functions, some fundamental visual processes have also been shown to be mediated by Cx HCs and Panx channels. In particular, two groups have demonstrated the involvement of these channels in visual processes in zebrafish. Between the two channels, Cx HCs were first implicated in synaptic transmission essential for vision (Kamermans and Fahrenfort, 2004; Klaassen et al., 2011). In the retina, Cx52.6 and Cx55.5 form GJ channels between horizontal cells, while Cx55.5 also form HCs at the tips of the horizontal cell dendrites and can open at physiological membrane potentials (Shields et al., 2007). Klaassen et al. (2011) generated zebrafish Cx55.5 mutant, with a stop codon in the first extracellular loop of Cx55.5 (C54X), which led to decrease in both, Cx55.5 expression on the tips of the horizontal cell dendrites, and HC currents from horizontal cells. They reported that the total gap-junctional surface was preserved, although alterations in Cx52.6 expression and in the general organization of gap-junctional plaques were found. This study investigated the negative feedback from horizontal cells to cones, essential for contrast enhancement in vision. In these mutants, light-induced feedback from horizontal cells to cones was significantly reduced (Figure 4A). As a consequence, these mutant zebrafishes exhibited impairment in contrast sensitivity (Figure 4B). Supported by a mathematical model, the authors suggested that current flowing through Cx HCs at the tips of horizontal cell dendrites actually exert an ephaptic modulation of synaptic transmission through activation of adjacent voltage-dependent Ca2+ channels in presynaptic photoreceptor terminals. Interestingly, they also reported an upregulation of Panx1 expression at the tips of the horizontal cell dendrites in these mutants, suggesting that it could be partly accountable for the residual 40% HC activity in the mutant. The same group later demonstrated that Cx55.5 HC currents possess an inward component that is active at physiological membrane potentials and extracellular Ca2+ levels (Sun et al., 2012). These studies suggest an unconventional role of horizontal cell Cx HCs in synaptic transmission in the retina, where a carp ortholog of mammalian Cx43 is also expressed among several other Cxs (Dermietzel et al., 2000). While similar mechanisms involving other Cxs and other CNS regions are yet to be investigated, these research findings further confirmed the dynamic nature of physiological roles of HCs in synaptic transmission leading to functional outcome, which in this case is visual acuity.


Connexons and pannexons: newcomers in neurophysiology.

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

Cx HCs and Panx1 channels have significant roles in synaptic transmission essential for vision. (A,B) Cx55.5 HCs are important for contrast sensitivity in zebrafish retina. (A) To measure light-induced feedback responses, cones were first saturated with a 20 μm spot of light. A full-field light flash induced an inward current in cones due to negative feedback from horizontal cells. Cx55.5 mutant (red) cones showed a decreased feedback response compared to wild-type (black), as shown in sample traces. (B) Optokinetic gain, as a measure of contrast sensitivity, was determined by dividing the eye movement velocity by the velocity of the stimulus over a range of contrast in zebrafish larvae. This was significantly decreased in mutant compared to wild-type zebrafish. (C–E) Reciprocal regulation between resting microglia and neuronal activity via Panx1 channels. (C) Glutamate uncaging was performed in the intact zebrafish larvae to evoke Ca2+ activities of tectal neurons within 20 μm around the uncaging point of 1 μm in the soma layer of the optic tectum. From the side of microglia facing the uncaging point (“unc”), the proportion of the number of bulbous normalized to all process tips (“Bulbousunc/Tipunc”) is shown for larvae injected with splice morpholino oligonucleotides (MO) 6-min before (clear) and 24-min (gray) and 59-min (black) after uncaging. The increased in bulbous endings is shown in control MO, but abolished in Panx1 expression downregulation MO1 and MO2. (D) Normalized intensities of Ca2+ activities (light response amplitude) of tectal neurons in vivo evoked by moving bars at indicated frequencies are shown. Response is significantly reduced in neurons after microglial contact (red filled vs. clear bars) as compared to non-contact (black filled vs. clear bars). Numbers of neurons examined are shown on bars. (E) Schematic diagram showing a proposed model of microglial modulations of neuronal activity via Panx1 channels. During neuronal activity, neurons secrete “find me” signal locally (ATP being a candidate) via Panx1 channels, which steer microglial processes toward them (from “Surveying” to “I”). Bulbous endings are then formed on these processes promoting contact with neurons (“II”). Upon such contact, neuronal activity is downregulated (“III”). **p < 0.01; ***p < 0.001. Adapted, with permission, from Klaassen et al. (2011) (A,B), Li et al. (2012) (C,D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219455&req=5

Figure 4: Cx HCs and Panx1 channels have significant roles in synaptic transmission essential for vision. (A,B) Cx55.5 HCs are important for contrast sensitivity in zebrafish retina. (A) To measure light-induced feedback responses, cones were first saturated with a 20 μm spot of light. A full-field light flash induced an inward current in cones due to negative feedback from horizontal cells. Cx55.5 mutant (red) cones showed a decreased feedback response compared to wild-type (black), as shown in sample traces. (B) Optokinetic gain, as a measure of contrast sensitivity, was determined by dividing the eye movement velocity by the velocity of the stimulus over a range of contrast in zebrafish larvae. This was significantly decreased in mutant compared to wild-type zebrafish. (C–E) Reciprocal regulation between resting microglia and neuronal activity via Panx1 channels. (C) Glutamate uncaging was performed in the intact zebrafish larvae to evoke Ca2+ activities of tectal neurons within 20 μm around the uncaging point of 1 μm in the soma layer of the optic tectum. From the side of microglia facing the uncaging point (“unc”), the proportion of the number of bulbous normalized to all process tips (“Bulbousunc/Tipunc”) is shown for larvae injected with splice morpholino oligonucleotides (MO) 6-min before (clear) and 24-min (gray) and 59-min (black) after uncaging. The increased in bulbous endings is shown in control MO, but abolished in Panx1 expression downregulation MO1 and MO2. (D) Normalized intensities of Ca2+ activities (light response amplitude) of tectal neurons in vivo evoked by moving bars at indicated frequencies are shown. Response is significantly reduced in neurons after microglial contact (red filled vs. clear bars) as compared to non-contact (black filled vs. clear bars). Numbers of neurons examined are shown on bars. (E) Schematic diagram showing a proposed model of microglial modulations of neuronal activity via Panx1 channels. During neuronal activity, neurons secrete “find me” signal locally (ATP being a candidate) via Panx1 channels, which steer microglial processes toward them (from “Surveying” to “I”). Bulbous endings are then formed on these processes promoting contact with neurons (“II”). Upon such contact, neuronal activity is downregulated (“III”). **p < 0.01; ***p < 0.001. Adapted, with permission, from Klaassen et al. (2011) (A,B), Li et al. (2012) (C,D).
Mentions: In addition to their contributions to synaptic and higher level brain functions, some fundamental visual processes have also been shown to be mediated by Cx HCs and Panx channels. In particular, two groups have demonstrated the involvement of these channels in visual processes in zebrafish. Between the two channels, Cx HCs were first implicated in synaptic transmission essential for vision (Kamermans and Fahrenfort, 2004; Klaassen et al., 2011). In the retina, Cx52.6 and Cx55.5 form GJ channels between horizontal cells, while Cx55.5 also form HCs at the tips of the horizontal cell dendrites and can open at physiological membrane potentials (Shields et al., 2007). Klaassen et al. (2011) generated zebrafish Cx55.5 mutant, with a stop codon in the first extracellular loop of Cx55.5 (C54X), which led to decrease in both, Cx55.5 expression on the tips of the horizontal cell dendrites, and HC currents from horizontal cells. They reported that the total gap-junctional surface was preserved, although alterations in Cx52.6 expression and in the general organization of gap-junctional plaques were found. This study investigated the negative feedback from horizontal cells to cones, essential for contrast enhancement in vision. In these mutants, light-induced feedback from horizontal cells to cones was significantly reduced (Figure 4A). As a consequence, these mutant zebrafishes exhibited impairment in contrast sensitivity (Figure 4B). Supported by a mathematical model, the authors suggested that current flowing through Cx HCs at the tips of horizontal cell dendrites actually exert an ephaptic modulation of synaptic transmission through activation of adjacent voltage-dependent Ca2+ channels in presynaptic photoreceptor terminals. Interestingly, they also reported an upregulation of Panx1 expression at the tips of the horizontal cell dendrites in these mutants, suggesting that it could be partly accountable for the residual 40% HC activity in the mutant. The same group later demonstrated that Cx55.5 HC currents possess an inward component that is active at physiological membrane potentials and extracellular Ca2+ levels (Sun et al., 2012). These studies suggest an unconventional role of horizontal cell Cx HCs in synaptic transmission in the retina, where a carp ortholog of mammalian Cx43 is also expressed among several other Cxs (Dermietzel et al., 2000). While similar mechanisms involving other Cxs and other CNS regions are yet to be investigated, these research findings further confirmed the dynamic nature of physiological roles of HCs in synaptic transmission leading to functional outcome, which in this case is visual acuity.

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