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ANESTHETIC PHARMACOLOGY

Central Nervous System Electrical Synapses as Likely Targets for Intravenous General Anesthetics

Department of Anesthesiology and Critical Care and the Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA

Address correspondence and reprint requests to Jonas S. Johansson, MD, PhD, 319C John Morgan Building, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104. Address e-mail to johanssj{at}uphs.upenn.edu.

Most investigations into the mechanisms of general anesthetic action focus on the effects of these drugs on the activity of ligand-gated ion channels, such as the -aminobutyric acid type A (GABA_A) receptor, the glycine receptor, and the excitatory ionotropic glutamate receptor that is activated by N-methyl-D-aspartate (1,2). These ligand-gated ion channels are responsible for fast chemical synaptic communication between neurons using the small neurotransmitter molecules -aminobutyric acid, glycine, and glutamate, respectively. Volatile anesthetics such as isoflurane and sevoflurane, enhance chloride conduction at the GABA_A- and glycine receptor, leading to hyperpolarization of the neuronal plasma membrane, effects that are also mediated by IV anesthetics such as the barbiturates and propofol. Depolarizing ion conduction through N-methyl-d-aspartate receptors, on the other hand, is not altered appreciably by the anesthetics mentioned above, but is inhibited by nitrous oxide, xenon, and ketamine.

Neurons can also communicate with their neighbors (both neurons and glia) via electrical synapses, or gap junction channels (Fig. 1). Information transfer is bidirectional and even faster than what can be achieved at a chemical synapse (3). An electrical synapse is composed of two hemichannels, which are integral plasma membrane protein complexes that dock with each other in the extracellular space to form a contiguous water-filled channel, impermeable to extracellular fluid components, connecting the cytoplasmic compartments of the two adjacent cells. Each hemichannel (connexon) is composed of a hexamer of individual proteins, called "connexins." There are 21 different connexin proteins represented in the human genome, of which 11 are expressed in the central nervous system (4–6). The different connexin proteins are identified using the abbreviation Cx followed by the molecular weight in kilodaltons (7). For example, connexin36 (Cx36) is expressed in inhibitory GABAergic interneurons and is responsible for the electrical coupling of these cells in the neocortex (8,9). Gap junction channels composed of different connexin protein dodecamers exhibit both unique channel gating properties and selectivities as far as concerns their characteristic permeabilities for small molecules and ions transmitted through the pore connecting the two adjacent cells. Each individual connexin protein has four transmembrane segments that have -helical secondary structure and which together form a four--helix bundle motif based on electron cryomicroscopy data of two-dimensional gap junction channel crystals at a 5.7 Å in-plane resolution (10). A cluster of these hemichannel pairs is responsible for the ultrastructural feature known as a "gap junction," as revealed and defined by electron microscopy studies in the 1960s (11).

View larger version (31K): [in this window] [in a new window]   Figure 1. (A) Schematic diagram showing two types of synapses present in the central nervous system. Gap junction channels (red) allow direct electrical coupling of Neurons 1 and 2. Ligand-gated ion channels (green) on Neuron 1 are activated by neurotransmitter (purple) released from synaptic vesicles by Neuron 2 at a chemical synapse. (B) Representation of a single connexon (hexamer of connexin proteins, also referred to as a hemichannel) contributed by one neuron. Each blue cylinder depicts a single connexin protein. Two such connexons come into contact in the extracellular space to form a functional gap junction channel. Yellow and black represents the plasma membrane. (C) Cartoon of a single connexin protein showing four transmembrane domains (M1-M4) that form the channel, two extracellular loops (involved in making connections with the corresponding domains from connexin proteins in the plasma membrane of a neighboring cell), and a cytoplasmic loop and N- and C-terminus domains (all of which are responsible for the gating properties and small molecule selectivity of the channel).

Because of their role in intercellular communication in the central nervous system, electrical synapses composed of different connexin protein dodecamers represent another plausible group of targets for general anesthetics, as reported in the paper by Wentlandt et al. (12) in this issue of Anesthesia & Analgesia. The authors found that both propofol and thiopental (at concentrations that are typically encountered in the anesthetized subject) depressed intercellular communication via gap junction channels in cultured hippocampal slices from 7-day old male Wistar rats, using a fluorescence recovery after photobleaching approach and electrophysiological measurements. In contrast, halothane was only able to inhibit gap junction channel function at high concentrations (on the order of 10 times the minimal alveolar concentration, MAC). The latter finding is in accord with earlier studies that examined the effect of halothane on cardiac ventricular myocyte gap junction channel permeability (mediated by connexin43 dodecamers), where halothane had effects only at concentrations of 2 mM or greater (13,14). However, Mantz et al. (15) reported that 100 µM halothane (approximately 0.4 MAC) inhibited gap junction channel function in primary cultures of rat striatal astrocytes by 75% using the fluorescent dye Lucifer yellow to quantify cell-to-cell communication, suggesting that the permeability of certain connexin protein dodecamers is modified by volatile anesthetics at the appropriate concentrations.

Gap junction channels permit the direct transmission of electrical signals between adjacent neurons, and therefore act to couple their plasma membrane potentials, increasing the likelihood of synchronized action potentials and oscillatory rhythmic activity at certain frequencies (16–18). Synchronized oscillations mediated by electrical synapses are thought to be responsible for higher neuronal function involved in memory formation, learning, and sensory perception (19). In agreement with this, a recent study on Cx36 knockout mice showed that both the power and the frequency of oscillations were affected, and that the animals displayed learning and memory deficits (20), as assessed by rotarod latencies and maze testing.

These direct cell-to-cell channels also allow the rapid exchange of small molecules (up to approximately 1,000 Daltons) between cells, including second messengers such as cyclic nucleotides and inositol phosphates, and metabolites such as glucose and amino acids. In the central nervous system, the expression of connexin genes is restricted to certain adult neuronal subpopulations. For example, in the neocortex, electrical synapses are formed exclusively between inhibitory GABAergic interneurons (9), while pyramidal cells are not electrically coupled.

Future studies will no doubt focus, in part, on providing a more detailed understanding of how general anesthetics alter gap junction channel gating and conduction properties, defining which connexin proteins are sensitive to which anesthetics, and also endeavoring to provide a detailed structural understanding of the interactions between these agents and the connexin proteins involved. However, since coordinated synchronous activity of groups of neurons in the central nervous system is thought to play a central role in more complex forms of information processing, such as memory formation, learning, and sensory perception, additional studies should also be performed on the effects of general anesthetics on the functioning of neural networks (21–23). Simultaneous investigations by different groups with expertise at different levels of biological complexity from isolated protein molecules on up to networks of interacting neurons are expected to provide a precise understanding of how these widely used clinical agents reversibly alter central nervous system function to induce the anesthetic state.

	Footnotes

 
Accepted for publication February 27, 2006.

Supported by NIH GM65218.

	References

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