Differential Expression of Sodium Channel β Subunits in Dorsal Root Ganglion Sensory Neurons

Ho, Cojen; Zhao, Juan; Malinowski, Steven; Chahine, Mohamed; O’Leary, Michael E.

doi:10.1074/jbc.m111.333740

Cited by 32 publications

(38 citation statements)

References 51 publications

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“…This approach may be especially attractive as three different types of b subunits are differentially and selectively expressed in small, medium, and large DRG neurons (Zhao et al, 2011;Ho et al, 2012).…”

Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacol Rev

292

251

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Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacol Rev

292

251

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“…34). Adding to this, it is now recognized that dorsal root ganglion (DRG) neurones can also express different markers, ChAT (choline acetyl-transferase), 37 sodium channel sub-types, 38 and lectin binding, 39 suggesting multiple types of afferent nerve. In the rat it is clear that a significant number of afferent fibers (Aδ and C fibers) express CGRP (calcitonin gene related peptide) and substance-P immuno-reactivity while in contrast C fibers express little NF (neurofilament) while all the Aδ fibers do 36 .…”

Section: Complex Afferent Outflow From the Bladdermentioning

confidence: 99%

The concept of peripheral modulation of bladder sensation

Eastham

Gillespie

2013

Organogenesis

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It is recognized that, as the bladder fills, there is a corresponding increase in sensation. This awareness of the volume in the bladder is then used in a complex decision making process to determine if there is a need to void. It is also part of everyday experience that, when the bladder is full and sensations strong, these sensations can be suppressed and the desire to void postponed. The obvious explanation for such altered perceptions is that they occur centrally. However, this may not be the only mechanism. There are data to suggest that descending neural influences and local factors might regulate the sensitivity of the systems within the bladder wall generating afferent activity. Specifically, evidence is accumulating to suggest that the motor-sensory system within the bladder wall is influenced in this way. The motor-sensory system, first described over 100 years ago, appears to be a key component in the afferent outflow, the afferent “noise,” generated within the bladder wall. However, the presence and possible importance of this complex system in the generation of bladder sensation has been overlooked in recent years. As the bladder fills the motor activity increases, driven by cholinergic inputs and modulated, possibly, by sympathetic inputs. In this way information on bladder volume can be transmitted to the CNS. It can be argued that the ability to alter the sensitivity of the mechanisms generating the motor component of this motor-sensory system represents a possible indirect way to influence afferent activity and so the perception of bladder volume centrally. Furthermore, it is emerging that the apparent modulation of sensation by drugs to alleviate the symptoms of overactive bladder (OAB), the anti-cholinergics and the new generation of drugs the β3 sympathomimetics, may be the result of their ability to modulate the motor component of the motor sensory system. The possibility of controlling sensation, physiologically and pharmacologically, by influencing afferent firing at its point of origin is a “new” concept in bladder physiology. It is one that deserves careful consideration as it might have wider implications for our understanding of bladder pathology and in the development of new therapeutic drugs. In this overview, evidence for the concept peripheral modulation of bladder afferent outflow is explored.

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“…β-Subunits are prominent members of the Na v channel signaling complex but do not contribute to the ion-conducting pore (5). Instead, they are multifunctional single-transmembrane segment glycoproteins that (i) modulate the gating properties of voltagegated ion channels; (ii) regulate Na v channel trafficking and expression levels; and (iii) promote cell adhesion and migration (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Of the four known β-subunits and their splice variants (15)(16)(17)(18)(19)(20), β4 is unique in that it enables resurgent current, a feature that renders certain Na v channel isoforms capable of high-frequency firing in excitable tissues (21).…”

mentioning

confidence: 99%

Crystallographic insights into sodium-channel modulation by the β4 subunit

Gilchrist

Das

Petegem

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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Voltage-gated sodium (Na v ) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, β-subunits modify Na v channel function and cause debilitating disorders when mutated. While investigating whether β-subunits also influence ligand interactions, we found that β4 dramatically alters toxin binding to Na v 1.2. To explore these observations further, we solved the crystal structure of the extracellular β4 domain and identified 58 Cys as an exposed residue that, when mutated, eliminates the influence of β4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of β4. Disrupting this bridge by introducing a β1 mutation implicated in epilepsy repositions the 58 Cys-containing loop and disrupts β4 modulation of Na v 1.2. Overall, the principles emerging from this work (i) help explain tissuedependent variations in Na v channel pharmacology; (ii) enable the mechanistic interpretation of β-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant β-subunit behavior.voltage-gated sodium channel | beta4 subunit | ProTx-II | X-ray structure | disease mutations

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Differential Expression of Sodium Channel β Subunits in Dorsal Root Ganglion Sensory Neurons

Cited by 32 publications

References 51 publications

Etiology and Pharmacology of Neuropathic Pain

Etiology and Pharmacology of Neuropathic Pain

The concept of peripheral modulation of bladder sensation

Crystallographic insights into sodium-channel modulation by the β4 subunit

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