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The disruptive effect of the singlet oxygen is highly focal, extending for only 5 nm. Together these data suggest that, while many features of the process are still imperfectly understood, it is becoming evident that microdomains are essential to axon targeting during brain development.
Important questions for future research include the identification of the specific intracellular pathways involved, the mechanics of pathway cross-talk, and the extent to which these cascades play a role in adult plasticity. In pursuing the latter questions, the relatively well-defined interactions involved in activity-dependent signaling to the nucleus via cyclic AMP response element binding protein CREB may possibly serve as a prototype.
The system is therefore important as a paradigmatic example of gene-brain reciprocal signaling in the biology of human behavior [ Hormone or growth-factor binding with microdomain-associated tyrosine kinase receptors initiates a signal cascade which generates inositol 1,4,5 triphosphate IP 3. If their model turns out to be correct, it would suggest that microdomain localization is essential for spatio-temporal coordination of protein dynamics on both the organelle and plasma-membrane levels.
The latter may be regarded as a node in a molecular network which, given its multiple targets, could have an amplifying effect. Cross-talk between these pathways is another probable means by which input to CREB, and consequent up- or down-regulation of gene transcription, may be rapidly effected. As Bonnie Lonze and David Ginty have suggested, it is plausible that maximal phosphorylation may be associated with maximal gene expression [ 46 ].
Building upon that premise, the various modulatory mechanisms appear consistent with the concept of gene-brain cross-talk facilitating adaptation in complex, changing environments.
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A full discussion of these systems is beyond the scope of this review. However, we may note that the final impression one takes away from these intricate, linked, and graded intracellular pathways is that of a hierarchy of evolutionarily optimized molecular regulators, at the apex of which is the neural membrane microdomain.
In contrast to the intensive research on microdomain involvement in intracellular signaling, there has been relatively less emphasis on the possible role of these structures in impulse propagation. The disparity is somewhat surprising, given the strong historical priority of research on the latter topic. According to the conventional model formally described in by Alan Lloyd Hodgkin and Andrew Huxley, and based on their experiments with the squid giant axon, the neural impulse or action potential AP is initiated and propagated by means of trans-membrane ion flux through protein channels which successively generates, along the axon, a reversal of membrane potential at each channel locus above a critical threshold, thus relaying the impulse [ 47 ].
Nearly six decades later, the Hodgkin-Huxley HH model, although subjected to occasional critiques, remains the widely accepted explanation for electrical signaling in the neuron. Moreover, it has strongly influenced formal mathematical modeling of the artificial neuron, to be discussed briefly in the following section. Although microdomain stabilization of ion channels and channel co-factors is clearly relevant to HH, there is at the time of this writing only one major study of microdomain modulation of ion-channel properties.
Importantly, cyclodextrin treatment of the non-microdomain-associated channel Kv4. The latter finding suggests that the modulation of Kv2. The study notes that Kv channels often contain phosphorylation sites, and that Kv2.
The observed inactivation effect may thus have resulted from cyclodextrin-induced separation of scaffolded signal components rather than from disruption of direct-microdomain-lipid interaction with the ion-channel protein. The Martens experiment, like most of the studies in this review, emphasizes the scaffolding function of microdomains.
Are there also intrinsic microdomain physical and chemical properties that modulate the activity of neural-membrane integral proteins, including in particular ion channels? To date, the answer is largely conjectural, suggesting a need for further research. Computer-simulation studies conducted by Harry Price and the author suggest that electric-field effects generated in the plane of the membrane during AP propagation may transiently alter microdomain physical properties in a manner that could modulate ion-channel activity, thereby altering neuron signaling [ 50 , 51 ]. On the basis of these and similar studies, we simulated the possible mechanical and electrostatic effects of an applied field on different membrane-lipid species.
In our initial study, we investigated how the alignment of unsaturated bonds of model compounds would affect field-responsive properties dipole and quadrupole moments, and polarizability. The results of our first model indicated a strongly increased sensitivity to field gradients as the number of unsaturated bonds is increased. In relation to this finding, a second, more complex, study investigated energetically-favorable clustering, and polarizability values, of model lipids including, importantly, sphingolipids.
It was found that sphingolipids display an energetically-favorable alignment of unsaturated bonds. In an actual neuron, the alignment would be in the plane of the bilayer. In addition, the aligned bonds of the sphingolipids displayed the highest polarizability of all model lipid clusters. We then intuitively proposed that, in a neuron, transient dipoles would be generated in the clustered sphingolipids of an ion-channel associated microdomain as a field effect of channel gating and the trans-membrane current.
We further suggested that the lipid dipoles would interact electrostatically with charge residues known to be present in an unfolded random coil ion-channel protein. Ion-channel closing i. It would be, of course, incautious to infer too much from a limited number of studies.
This possibility will be examined in more detail in the discussion of artificial intelligence. The final stage of AP propagation is the relay of impulses into the neuron terminal, an event which generates intricate but temporally- and spatially-coordinated synaptic-transmission processes that are the basis of inter-neural signaling. In outline, synaptic transmission consists of the exocytosis of transmitter substance from lipid vesicles transiently fused with the pre-synaptic-terminal plasma membrane; the exocytosed neurotransmitter binds with post-synaptic receptors, resulting in target membrane depolarization, and continued AP propagation.
Increasing evidence suggests that certain features of exocytosis may be microdomain-regulated [ 56 — 58 ]. It is important to note, however, that several aspects of the process are not well understood, and the richness of scenarios has occasionally surpassed that of the data. Vesicle movement from the interior pool to the RRP is mediated by synapsin.
This phosphoprotein is vesicle-associated and bound to actin; the latter may provide a scaffold for interior-reserve vesicles. Synapsin is phosphorylated by several different kinases including CaMKII and protein kinases A and C , which causes it to dissociate from the interior reserve pool and translocate to the active zone of the presynaptic terminal plasma membrane docking stage.
Tangles Turn Neuronal Membranes Inside Out, Give Microglia License to Eat Their Fill
The steps involved in the latter process remain somewhat undefined, but it is possible that the vesicles may partially fuse with the plasma membrane, and that the energy derived from ATP hydrolysis may alter the conformation of proteins comprising the exocytic machinery. Synaptotagmin may undergo an electrostatic rather than conformational change, causing it to interact with an elaborate vesicle-and plasma-membrane-associated protein machinery—the much-analyzed SNARE complex—that directly induces membrane fusion and transmitter exocytosis.
On purely intuitive grounds, it would seem that SNARE complex function would require microdomain localization of its protein components for rapid assembly, coordinated function, and disassembly. But artificial-membrane and in vivo membrane data are highly inconsistent, contrasting noticeably with the greater convergence in the SNARE-protein imaging studies [ 60 — 62 ].
A closer look at neuron interaction with track-etched microporous membranes | Scientific Reports
Interpretations of microdomain modulation of exocytosis are thus an uneasy blend of consensus and speculation. The role of microdomains in subsequent vesicle and plasma membrane fusion has been the subject of much speculation. In what is clearly a programmatic article, the exact opposite scenario is also proposed, and other models are suggested as well. Exocytosed transmitter substances bind with a wide variety of post-synaptic receptors.
It is becoming increasingly clear that microdomain and liquid-disordered membrane regions help regulate receptor function by alternately segregating and co-localizing receptor signal components; moreover, microdomains may also play an active role in receptor conformational changes essential for transmitter binding [ 64 — 67 ].
These functions have been investigated in a number of prototype systems, especially AMPA, acetylcholine, and serotonin. Calcium entry in turn generates a cascade of LTP-associated events. Once recruited, AMPA receptors may be phosphorylated by microdomain-associated Trk, possibly altering AMPA receptor activity levels and thereby modulating synaptic plasticity.
But is it possible that microdomains affect receptor dynamics in a more direct way? In the case of the acetylcholine receptor, a wide variety of imaging studies indicate that its microdomain environment is subdivided into bulk and shell lipids, both in a liquid-ordered phase. The shell component immediately surrounds the receptor, restricting its mobility for possible protein-cholesterol interaction. Sphingolipids may also be essential to effective acetylcholine-receptor function.
Structural studies of a wide range of proteins indicate a sphingolipid binding domain SBD , comprised of amino acid residues which bind to the polar headgroup of the sphingolipid. Based upon these data, and recent infrared and ultraviolet spectroscopy evidence for eight low-energy conformational isomers of serotonin [ 70 ], the investigators propose that interaction between cholesterol, sphingolipids, and the G protein-coupled serotonin receptor may regulate ligand binding and receptor-mediated signaling. Microdomain sphingolipids, which display remarkable conformational variety numbering in the hundreds of shapes due to chain length, degree of saturation, and head-group structure, would play a determinative role in fashioning a distinctive shape for the serotonin molecule.
The computational implications of the Fantini-Barrantes model are worth considering. In essence, their viewpoint appears consistent with a concept of sub-neural information-processing modules in which the tokens are a set of interacting molecules seeking a minimum local potential energy. Receptor-channel gating and subsequent field-induced lateral movement of sphingolipids between post-synaptic microdomains, possibly by hop diffusion over cytoskeleton barriers, would modulate the computation, thus amounting to a form of learning.
Possibilities such as these reflect the growing conceptual richness of microdomain theory, now entering its third decade. They also suggest a role for molecular-machine mimics in extending current models of artificial intelligence. This strategy will be discussed briefly in the following section. This review has evaluated a rapidly growing body of evidence suggesting that neural-membrane microdomains may function as dynamic scaffolds which co-localize signal units, thereby modulating neuron electrochemical information.
These data, if reinforced by future investigations, may have important implications for the understanding of how the neuron works. In an admittedly speculative vein, but consistent with available data, it is here proposed that the neuron is not the fundamental unit of brain information-processing; rather, the neuron is more accurately regarded as a linear array of microdomain computational modules which can propagate, amplify, and indeed extinguish an AP, based on moment-to-moment changes in lipid composition and lipid-protein interactions [ 71 ].
As well, microdomains may up- or down-regulate intracellular molecular signals including, importantly, signaling to the nucleus. This approach is clearly at variance with the foundations of artificial intelligence. In their mathematical model, the neuron computed a weighted sum of inhibitory and excitatory inputs with regard to a threshold value, fired if inputs were at or above threshold in an all-or-none fashion, and propagated an invariant signal to another target unit.
This view, which has given rise to many intellectual descendants—including the units in neural-network, perceptron, and connectionist theory—remains the key mathematical concept underlying formal modeling and physical implementation of neuropsychological processes. Yet, as several researchers have noted based largely on extensive evidence for signal modulation in dendrites, as well as groups of synapses that depress nearest-neighbor activity the neuron may not be analogous to a gate composed of a single transistor [ 73 — 75 ].
Instead, consistent with the viewpoint presented in this article, the neuron is more properly analogized to a chip or integrated circuit comprised of interconnected transistors. Can molecular-machine mimics of neural membrane microdomains contribute to more realistic, computationally subtle models in neural networks and artificial intelligence? The answer is guardedly affirmative because, although much has been accomplished, significant engineering obstacles remain [ 76 — 81 ].
The most promising architectures for investigating signal-protein interactions and ion-channel functioning in microdomains are mobile planar lipid bilayers on solid supports such as gold or silicon Figure 3. Ion-channel insertion, measurable ion flow, and membrane lateral mobility are best achieved by decoupling the membrane from the support by means of a water layer or hydrated polymer. The latter, a biomimic of the cytoskeleton, can stabilize the system for analysis while sacrificing some lateral mobility if the polymer layer is covalently tethered to the substrate and attached to the membrane by anchor lipids.
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Channel-forming proteins have been inserted into engineered membranes with varying levels of biological realism. Traditionally, gramicidin A—a dimer synthesized by binding immobile and mobile half-channels to create a conducting channel—has been widely used as an ion-channel model system. Although this strategy continues, interest in alternative models has been stimulated by the recent successful insertion of functioning glutamate-receptor ion channels mostly NMDA type into a mixed hybrid bilayer membrane [ 82 ].
Supported lipid bilayer highly schematic. Supports are typically gold or silicon. The membrane may be decoupled from the support by a water layer shown or a hydrated polymer. For stabilization, the latter structure is typically attached to the membrane by anchor lipids, and covalently tethered to the substrate. Functioning ion-channels can be inserted into the membrane. An important research goal is the synthesis of increasingly realistic supported membranes comprised of microdomains with interstitial liquid-disordered non-raft regions.
Another potentially valuable study would examine microdomain effects on the voltage-gated A-current potassium channel K A. Members of this microdomain-localized channel vary in their kinetics and voltage dependence, but share a critical property: they are transiently activated by depolarization following a period of hyperpolarization [ 83 ]. This feature has the important consequence of increasing local hyperpolarization, frequently resulting in AP propagation failure. If K A kinetics in an artificial system can be directionally modulated by the microdomain environment e.
Studies along these lines could potentially motivate the development of novel architectures perhaps departing significantly from the traditional McCulloch-Pitts neuron in neural networks and artificial intelligence. Frequently misunderstood by early cell biologists due to flawed instrumentation and inaccurate paradigms, the cell membrane is now widely recognized as an important regulatory structure. The microdomain or raft in particular is increasingly viewed as a molecular scaffold which co-localizes signal proteins for orchestrating extra- and intracellular molecular processes.