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Review
. 2015 Aug;72(15):2823-51.
doi: 10.1007/s00018-015-1962-7. Epub 2015 Jun 29.

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Elke Decrock  1 , Marijke De Bock, Nan Wang, Geert Bultynck, Christian Giaume, Christian C Naus, Colin R Green, Luc Leybaert
Affiliations
Review

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Elke Decrock et al. Cell Mol Life Sci. 2015 Aug.

Abstract

The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. C.R.G is a founding scientist of CoDa Therapeutics, Inc. which has intellectual property related to connexin channel modulation for therapeutic purposes.

Figures

Fig. 1
Fig. 1
Schematic representation of the neuro-glio-vascular unit. The NGVU consists of neurons, the blood vessels that supply them with energy substrates, and glial cells. Astrocytes mediate communication between the vasculature and neurons by projecting their processes toward the neuronal synapse and their endfeet onto the blood vessels. Cerebral arteries and larger arterioles are separated from the brain parenchyma by the perivascular space, a basement membrane and the astrocytic endfeet. As the arterioles penetrate deeper into the brain, the perivascular space gradually disappears and the blood vessels come into direct contact with the astrocytic endfeet. The term NGVU refers to the close structural and functional relationship between brain cells and vascular cells, which is crucial for homeostatic signaling to occur within the CNS. SMCs smooth muscle cells
Fig. 2
Fig. 2
Structure of connexin and pannexin proteins, and the channels they form. Cx and Panx proteins share a similar topology. Both proteins contain four transmembrane domains, two extracellular loops (EL1-2), one intracellular loop (IL), one intracellular amino-terminus (NT), and one carboxy-terminus (CT). Six Cx or Panx proteins oligomerize into a HC or Panx channel, respectively. Of note, Panx2 has been proposed to form octameric channels [60]. At cell–cell contact regions, two HCs dock to form a GJC. In contrast, all three Panxs are glycosylated (G) at their EL, which is suggested to interfere with docking of apposed Panx channels, thus excluding GJC formation. EC extracellular, IC intracellular
Fig. 3
Fig. 3
Connexin-mediated and pannexin-mediated signaling pathways at the neuro-glio-vascular unit. 1 At the electrical synapse, GJCs, mainly composed of Cx36, allow the direct bidirectional passage of electrical signals carried by ions, as well as small metabolites and messenger molecules between neurons. 2 At the chemical synapse, neurotransmitters released from presynaptic neurons bind to their corresponding receptors on the postsynaptic membrane. Panx1 channels, present at the postsynaptic membrane, can be opened by NMDAR activity. The inward current flow via Panx1 channels subsequently results in depolarization, while the release of substances such as ATP or glutamate may affect the postsynaptic as well as presynaptic membrane potential via the activation of their corresponding receptors. One study has reported the presence of neuronal Cx36HCs that are involved in ischemic tolerance via the release of ATP. 3 There is a bidirectional communication and regulation between electrical and chemical synapses in the developing and mature CNS. 4 Neurotransmitters released in the synaptic cleft are taken up by astrocytic transporters and distributed over the astrocytic network through Cx30/Cx43 GJCs. GJIC is furthermore important for the spatial buffering of potassium and the delivery of energy substrates to regions of high neuronal demand. 5 Cx30 can influence glutamate clearance in a channel-independent manner (presented here by a single Cx protein in the membrane) by modulating astrocyte morphology and the presence of astrocytic processes in the synaptic cleft. 6 Neurotransmitter receptors, such as mGluR5 and the NMDAR, are present in astrocytic membranes. The activation of both receptors results in astrocytic [Ca2+]i increases, a known trigger for HC/Panx1 channel opening, thereby evoking the subsequent release of gliotransmitters that can feedback to the neuronal synapse and affect (extra)synaptic neuronal activity, neuronal circuit plasticity, and survival. 7 [Ca2+]i increases can be propagated to neighboring cells via two parallel pathways (dashed lines), namely IP3 diffusion through GJCs, and ionoptropic or metabotropic receptor activation by gliotransmitter molecules. 8 Astroglial [Ca2+]i increases can activate HCs/Panx1 channels in the astrocytic endfeet which can result in the release of vasoactive substances that act at the level of the smooth muscle cells (SMCs), resulting in vasoconstriction or vasodilation. 9 [Ca2+]i increases can be propagated through perivascular endfeet via GJCs and/or the action of vasoactive substances, such as ATP, on plasma membrane receptors on neighboring astroglial cells (dashed lines). It is speculated that calcium signaling in the astroglial endfeet may play a role in functions related to the vasculature, including barrier function, blood flow regulation, metabolic trafficking, and water homeostasis. 10 The absence of Cx30 and astroglial Cx43 results in swollen endfeet, a reduction in aquaporin-4, a differential expression of components of the dystrophin complex, and a disrupted BBB under conditions of increased hydrostatic vascular pressure or shear stress. 11 At the level of the endothelial cells, GJCs are suggested to contribute to normal BBB function, while the opening of HCs rather triggers barrier dysfunction for example via the activation of an autocrine purinergic pathway, evoking calcium oscillatory behavior. 12 These increases in [Ca2+]i can be propagated through the endothelial layer to upstream arterioles, thereby inducing retrograde vasodilation. 13 Microglia are considered to be part of the quadripartite synapse as neuronal activity can regulate microglial morphology and motility primarily through the release of ATP. Subsequent HC or Panx1channel opening can result in ATP or glutamate release that, in turn, may affect neuronal activity
Fig. 4
Fig. 4
Migration of excitatory neurons and inhibitory interneurons to the cortical plate. Excitatory cortical neurons originate in the ventricular zone (VZ) and migrate radially along radial glia to the cortical plate (CP). In contrast, the majority of the GABAergic neurons is generated in the ganglionic eminence (GE) of the ventral telencephalon and reach the cortical plate by first migrating tangentially (without radial glia) and then switching to radial migration. The tangential migration is mainly restricted to two streams, one within the marginal zone (MZ) and one within the subventricular (SVZ)/intermediate (IZ) zone. Cx43 plays an important role in the migration of both types of neurons in the embryonic cerebral cortex. More specifically, radial migration and the switch from tangential to radial migration are dependent on Cx43 adhesive properties and/or the interaction of the CT with components of the cytoskeleton, but do not rely on functional channel activity
Fig. 5
Fig. 5
Center–surround antagonism in the retina and the role of HCs and Panx1 channels herein. a Center–surround antagonism is illustrated for a ON center bipolar cell (ON BC). Cones in the center make direct synaptic contact with the ON BCs, while cones in the surround make synaptic contact with horizontal cells (HorCs) that indirectly act on these ON BCs via the cones in the center. Hence, signals from cones in the surround are funneled via HorCs to cones in the center. In the absence of light, the cone photoreceptors are depolarized (membrane potential around -35 mV) and provide a constant release of glutamate which maintains ON BCs in a hyperpolarized state via the activation of mGluR6. When the center receptive field receives a light stimulus, this triggers a hyperpolarization of the center cones ➊, a decrease in basal glutamate release from the cone pedicle, a depolarization of ON BCs ➋ and an increased firing of the ON-center ganglion cells (ON GC) ➌. When the surround receptive field receives a light stimulus, opposite postsynaptic responses take place. First, the cone in the surround field is hyperpolarized ①. Due to less glutamate release from the cones in the surround field, HorCs are hyperpolarized as well ②. Consequently, cones in the center field depolarize ③, resulting in an increase in glutamate release, a hyperpolarization of ON BCs ④, and a decreased firing of the ON GCs ⑤. The receptive field center response is thus suppressed by stimulation of the surround. b Magnification of the pink frame in panel a. HCs and Panx1 channels can contribute to two different HorC-driven antagonistic pathways, namely via ephaptic and proton-mediated interaction, respectively. Ephaptic transmission relies on an alteration in the excitability of cones due to electric fields that are generated by a HorC proximal to the cone. HCs on horizontal dendrites open with HorC hyperpolarization and allow inward current flow [158]. When the retina receives a light stimulus in the surround receptive field, the hyperpolarization of HorCs ② increases the inward current flow through the HCs, resulting in an increased negativity of the synaptic cleft. As a result of the membrane capacity, an extracellular negativity attracts a positive charge at the intracellular side of the cone. This is detected by the voltage sensor of L-type calcium channels in the membrane of the cone, resulting in more calcium influx in the cone, a depolarization of the cone ③ and glutamate release. This triggers hyperpolarization of ON BCs ④ by the activation of mGluR6. The second feedback pathway is based on the release of ATP via Panx1 channels. When HorCs hyperpolarize ②, the ATP release through Panx1 channels is reduced. As a result, less ATP is converted by ecto-ATPase enzymes to inosine, phosphate and proton ions. A decline in proton ion production induces an alkalinization of the synaptic cleft that is detected by voltage-dependent calcium channels in the membrane of the cone, again resulting in more calcium influx via these channels, a depolarization of the cone ③ and glutamate release. HCs and Panx channels thus contribute to two different mechanisms of center-surround antagonism, a very fast ephaptic and a relatively slow proton-mediated mechanism. RS ribbon synapse
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