title: Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles.
abstract: Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles.NEW & NOTEWORTHYThe molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons.
authors.affiliation: School of Biological Science, Georgia Institute of Technology, Atlanta Georgia.
authors.forename: Dario I
authors.initials: DI
authors.lastname: Carrasco
authors.affiliation: School of Biological Science, Georgia Institute of Technology, Atlanta Georgia.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Vincent
authors.affiliation: School of Biological Science, Georgia Institute of Technology, Atlanta Georgia; tim.cope@gatech.edu.|Biomedical Engineering, Georgia Institute of Technology, Atlanta Georgia; and.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cope
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002415:Cats; D005727:Ganglia, Spinal / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D016900:Neurofilament Proteins / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C051774:neurofilament protein H; D013779:Tetrodotoxin
keywords: immunohistochemistry; muscle spindle; sensory encoding; voltage-gated sodium channels