Muscle spindle afferents and the mystery of the α3isoform of Na+,K+-ATPase
Year: 2010
Type: article
Abstract: Normal nervous system function is critically dependent upon Na+,K+-ATPase activity. The functional Na+,K+-ATPase, a complex of α, β and γ protein subunits, hydrolyses ATP to exchange intracellular Na+ for extracellular K+. Thus, the transporter sets and maintains Na+ and K+ gradients controlling the resting membrane potential and neuronal excitability. Because of unequal exchange of K+ for Na+, Na+,K+-ATPase is an electrogenic mechanism that adds to the generation of hyperpolarizing afterpotentials when activated, thus modulating the frequency and duration of neuronal discharges. The Na+,K+-ATPase is the major mechanism preventing extracellular accumulation of K+ and associated hyperactivity of neuronal networks and centres. Despite such profound involvement in basic nervous function, many aspects of active ion transport by Na+,K+-ATPase within the nervous system are poorly understood. One unresolved matter concerns neuron-specific expression of the α3 isoform of the Na+,K+-ATPase (Dobretsov & Stimers, 2005). All major catalytic and transport properties of the Na+,K+-ATPase are determined by the α subunit. In mammals there are four known isoforms of the α subunit. An exceptional feature of the nervous system is that, in addition to ubiquitous α1 Na+,K+-ATPase, cells may also express α2 and α3 isozymes. Furthermore, the α3 isozyme is expressed by only a small subset of neurons, and not at all by glia or any other cells outside of the nervous system. In humans, missense mutations in the α3 Na+,K+-ATPase gene result in dystonia with addition of some Parkinsonian symptoms (de Carvalho et al. 2004). Mice with a genetic deficiency of functional α3 Na+,K+-ATPase display signs of severe motor impairment (Clapcote et al. 2009). Thus, in the nervous system, the α3 Na+,K+-ATPase plays a unique and critical role that apparently cannot be compensated for by up-regulation of other isoforms of the Na+,K+-ATPase. However, despite at least two decades of research already, the essence of this unique role of the α3 Na+,K+-ATPase remains a mystery (Lingrel, 1992; Dobretsov & Stimers, 2005). The major obstacle in answering the question above was the lack of a preparation allowing studies that directly compare the characteristics of the discharge of functionally identified neurons with the type and biophysical properties of isoforms of Na+,K+-ATPase expressed by these neurons. The structural and functional complexity of the nervous system complicates such comparisons. Recent immunohistochemical experiments suggested that the dorsal root ganglion (DRG) may provide such a preparation because the majority of primary afferent neurons express α1, while only the largest myelinated neurons express α1 and α3, or only α3 Na+,K+-ATPase (Dobretsov et al. 2003). However, the problem with these studies was that they suggested but did not allow definite classification of α3 Na+,K+-ATPase-expressing DRG neurons. The report by Parekh et al. (2010) in this issue of The Journal of Physiology closes this gap in the previous studies by functionally identifying these neurons as muscle spindle afferents. Using in vivo recordings and various peripheral stimuli the authors have shown that in both rat and guinea pig, antibodies for α3 Na+,K+-ATPase label the plasma membrane of neurons that were responding to muscle stretch and vibratory stimuli only. The findings of this work (Parekh et al. 2010) are of special importance for three main reasons. First, it opens a new avenue for general studies of the functional significance of neuronal expression of α3 Na+,K+-ATPase. Considering that DRG neurons are among the most accessible to various experimental approaches and there is a wealth of background information with respect to their development, physiological and biochemical characteristics, it should be expected that these neurons would be especially suited for studies linking neuronal function with the activity of isoforms of the Na+,K+-ATPase. Second, the biophysical properties of Na+,K+-ATPase are determined not only by its molecular structure but also by cellular factors and characteristics of lipid bilayer. Thus far, however, our knowledge of biophysical properties of neuronal α3 Na+,K+-ATPase is based mostly on the results of cell transfection experiments. Identification of muscle spindle afferents as natural host cells for α3 Na+,K+-ATPase, identifies these neurons also as a natural preparation for patch-clamp studies of its affinity to Na+, K+ and ATP and voltage dependence of its cycle in its native cell. Finally, confirmation of muscle spindle-associated expression of α3 Na+,K+-ATPase constitutes an important step in our understanding of physiology of stretch reflexes and associated circuits for the control of movement. Abnormal inflow and/or processing of peripheral proprioceptive information constitute an important component of pathogenesis of dystonia and it could be an essential part of pathogenesis of rapid-onset dystonia-Parkinsonism syndrome as well. The findings of Parekh et al. may also suggest a role of abnormalities in α3 Na+,K+-ATPase in age- and neurodegenerative disease-associated loss of deep tendon reflexes. Future studies will be essential for expanding on these important areas.
Source: The Journal of Physiology
Authors: Maxim Dobretsov, Joseph R. Stimers
Institution: University of Arkansas for Medical Sciences
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1968470326