Differential subcellular distribution of ion channels and the diversity of neuronal function

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Following the astonishing molecular diversity of voltage-gated ion channels that was revealed in the past few decades, the ion channel repertoire expressed by neurons has been implicated as the major factor governing their functional heterogeneity. Although the molecular structure of ion channels is a key determinant of their biophysical properties, their subcellular distribution and densities on the surface of nerve cells are just as important for fulfilling functional requirements. Recent results obtained with high resolution quantitative localization techniques revealed complex, subcellular compartment-specific distribution patterns of distinct ion channels. Here I suggest that within a given neuron type every ion channel has a unique cell surface distribution pattern, with the functional consequence that this dramatically increases the computational power of nerve cells.

Highlights

► The subcellular distribution of ion channels determines their functional roles. ► Novel localization techniques are used to study the distribution of ion channels. ► Each examined ion channel subtype has a unique distribution in pyramidal cells. ► This complex distribution patterns increase the computational power of nerve cells.

Introduction

Morphologically, neurons are the most complex cells of our body; the total length of their neurites might exceed hundreds of thousands of micrometers, and can contain thousands of branch points, axon terminals and dendritic spines. This morphological complexity of axonal and dendritic arbors has fascinated neuroscientists for more than a century, and has been the main tool for categorizing neuron types and predicting their presynaptic and postsynaptic elements within the neural circuit [1]. In the 1890s Ramon y Cajal formulated the Law of Dynamic Polarization, which states that a neuron receives signals at its dendrites and cell body, and transmits them along the axon away from the cell body. Although we now know that the Law of Dynamic Polarization does not hold true for all neurons under all conditions (i.e. backpropagating action potentials into the dendrites, retrograde signaling from soma/dendrite to the axon), the recognition of different functional roles of dendrites and axons was a major advancement in the history of neuroscience. In order to serve distinct functions, the molecular composition of the dendrites must be different from that of the axons. As the major site of protein synthesis is the soma, this necessitates the selective and appropriate transportation of somatically synthesized proteins into axons and dendrites. Selective sorting of plasma membrane proteins has been observed in many epithelial cells of luminar organs, resulting in a polarized distribution of proteins [2]. Analogous to this, nerve cells have often been considered as simple polarized cells, where axons and somata/dendrites represent the basolateral and apical domains, respectively. According to such a scheme, an expressed protein could take up any of the following three distribution patterns: 1) somato-dendritic, 2) axonal and 3) axo-somato-dendritic. This view predicts that because nerve cells express hundreds of distinct cell surface proteins, many of them must have the same distribution pattern.

In theory, the subcellular distribution of a protein can be described as a function of its ‘presence’ or ‘absence’ in each functionally relevant subcellular compartment of the cell. Thus, if a nerve cell contained more functionally relevant subcellular compartments than just the ‘axon’ and ‘somata/dendrites’, the total number of distinct distribution patterns would increase. If, for example, nerve cells had 5 functionally distinct subcellular compartments (e.g. 1: axon terminals, 2: axon initial segment (AIS), 3: soma, 4: dendritic shafts, 5: dendritic spines), ion channels could have 31 distinct subcellular distribution patterns. This calculation assumes either the ‘presence’ or ‘absence’ of a protein in either of these compartments. If, however, the protein could be ‘absent’, ‘present at low density’ or ‘present at high density’, the total number of distribution patterns would increase to 242. Most nerve cells with complex axonal and dendritic morphologies contain many more functionally relevant compartments than the two or five mentioned above. Functional studies demonstrated that hippocampal pyramidal cells (PCs) contain around two dozen relevant compartments, including presynaptic active zones; non-synaptic axon terminals; pre-terminal axons; nodes of Ranvier; AISs; somata; basal dendritic shafts and spines; main apical dendrites, oblique dendrites and dendritic spines in the proximal and distal stratum radiatum; dendritic shafts and spines in the stratum lacunosum-moleculare; excitatory postsynaptic densities to Schaffer collaterals and to the perforant path; inhibitory postsynaptic densities to many distinct GABAergic interneurons. It is easy to conceive that the total number of permutations, even if we only consider the binary ‘presence’ or ‘absence’ of an ion channel in each of these compartments, exceeds the total number of genes of our body. Thus, in theory, each cell surface protein could have a unique subcellular distribution pattern on the surface of a nerve cell.

Section snippets

Techniques for studying the subcellular distribution of ion channels

Almost two decades ago, Stuart et al. [3] developed the method of patch-pipette recording from small subcellular compartments, including the axon initial segment and apical dendrites of PCs. Since then, a large body of experimental data have been obtained with this technique, revealing the densities of distinct ligand-gated and voltage-gated ionic currents in a number of different subcellular compartments of many cell types (reviewed by [4, 5, 6, 7]). A great advantage of patch-pipette

Unique distribution patterns of distinct ion channel subunits in CA1 PCs

More than a decade ago, Magee [11••] performed dendritic patch-pipette recordings and found an increase in the density of hyperpolarization activated mixed cation current (Ih) along the proximo-distal axis of the apical dendrites of CA1 PCs. Because Ih is mediated by HCN1/2 subunits in CA1 PCs, we investigated the subcellular distribution of HCN1 using a preembedding EM immunogold technique [12] with special reference to its relative densities in proximal and distal dendritic shafts and spines.

Conclusions

In conclusion, recent experiments using high-resolution immunolocalization techniques revealed that all ion channels studied to date show distinct subcellular distribution patterns on the surface of CA1 PCs. This complex ion channel subtype-specific distribution raises many exciting cell biological and neurobiological questions. It will be interesting to see how nerve cells can achieve a unique subcellular distribution pattern for each expressed ion channel. It is predicted that each channel

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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