Dario I. Carrasco, PhD
School of Biological Sciences
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 we tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. We began study of the NaV1.6 isoform, selected both for its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. We found NaV1.6 immunoreactivity (IR) concentrated in heminodes, where tonic firing is presumably generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals where mechano-transduction occurs. We established consistency in this spatial pattern of NaV1.6 IR distribution for three mammalian species (rat, cat, and mouse) and went on to verify that primary spindle afferents in all three species fire tonically. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. We extended study to two additional NaV isoforms, selected for their sensitivity to tetrodoxin (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 NaV1.6, and for NaV1.7 mainly in pre-terminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles.