Abstract
Retinal ganglion cells (RGCs) are projection neurons that transmit the visual signal from the retina to the brain. Their excitability and survival can be strongly influenced by mechanical stressors, temperature, lipid metabolites, and inflammatory mediators but the transduction mechanisms for these non-synaptic sensory inputs are not well characterized. Here, we investigate the distribution, functional expression, and localization of two polymodal transducers of mechanical, lipid, and inflammatory signals, TRPV1 and TRPV4 cation channels, in mouse RGCs. The most abundant vanilloid mRNA species was Trpv4, followed by Trpv2 and residual expression of Trpv3 and Trpv1. Immunohistochemical and functional analyses showed that TRPV1 and TRPV4 channels are expressed as separate molecular entities, with TRPV1-only (∼10%), TRPV4-only (∼40%), and TRPV1 + TRPV4 (∼10%) expressing RGC subpopulations. The TRPV1 + TRPV4 cohort included SMI-32-immunopositive alpha RGCs, suggesting potential roles for polymodal signal transduction in modulation of fast visual signaling. Arguing against obligatory heteromerization, optical imaging showed that activation and desensitization of TRPV1 and TRPV4 responses evoked by capsaicin and GSK1016790A are independent of each other. Overall, these data predict that RGC subpopulations will be differentially sensitive to mechanical and inflammatory stressors.
Highlights
Vertebrate vision is based on separating photon input from background thermal energy and extraction of luminance, local contrast, color, orientation, direction of motion, and “looming” information from the visual scene (Lettvin et al, 1959)
RNA profiling shows that mouse retinal ganglion cells (RGCs) express all four thermoTrp transcripts (Trpv1-4) (Figure 1A), with expression dominated by Trpv4, followed by Trpv2, Trpv3, and Trpv1 mRNAs, respectively (Figure 1B)
TRPV4−/− RGCs showed a trend toward Trpv1 upregulation but these changes were not significant (Figure 1C)
Summary
Vertebrate vision is based on separating photon input from background thermal energy and extraction of luminance, local contrast, color, orientation, direction of motion, and “looming” information from the visual scene (Lettvin et al, 1959). Transient receptor potential (TRP) vanilloid channels are polymodal cation channels that function as molecular integrators of many types of sensory input (Clapham, 2003; Nilius and Szallasi, 2014). TRPV1-4 ( known as thermoTRPs for their temperature sensitivity) are non-selective cation channels whereas TRPV5 and TRPV6 are predominantly permeable to Ca2+ and typically expressed in epithelial and bone cells (Clapham, 2003). The most studied vanilloid isoforms are TRPV1 and TRPV4, with ∼50% sequence homology and activation by distinct agonists, temperature ranges, mechanical, osmotic, and inflammatory stressors (Martins et al, 2014; Nilius and Szallasi, 2014). Inflammatory agents sensitize TRPV1/4 channels by mechanisms that are not fully defined whereas selective inhibition or deletion of TRPV1- and TRPV4expressing neurons produces burning, freezing, itch, mechanical pain, and thermosensory phenotypes together with loss of osmoregulation and hearing loss (Caterina et al, 1997; Tominaga et al, 1998; Liedtke and Friedman, 2003; Alessandri-Haber et al, 2004)
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