Abstract
Transient receptor potential (TRP) channels constitute a large family of cation permeable ion channels that serve crucial functions in sensory systems by transducing environmental changes into cellular voltage and calcium signals. Within the retina, two closely related members of the melastatin TRP family, TRPM1 and TRPM3, are highly expressed. TRPM1 has been shown to be required for the depolarizing response to light of ON-bipolar cells, but the role of TRPM3 in the retina is unknown. Immunohistochemical staining of mouse retina with an antibody directed against the C-terminus of TRPM3 labeled the inner plexiform layer (IPL) and a subset of cells in the ganglion cell layer. Within the IPL, TRPM3 immunofluorescence was markedly stronger in the OFF sublamina than in the ON sublamina. Electroretinogram recordings showed that the scotopic and photopic a- and b-waves of TRPM3-/- mice are normal indicating that TRPM3 does not play a major role in visual processing in the outer retina. TRPM3 activity was measured by calcium imaging and patch-clamp recording of immunopurified retinal ganglion cells. Application of the TRPM3 agonist, pregnenolone sulfate (PS), stimulated increases in intracellular calcium in ~40% of cells from wild type and TRPM1‑/‑ mice, and the PS-stimulated increases in calcium were blocked by co-application of mefenamic acid, a TRPM3 antagonist. No PS-stimulated changes in fluorescence were observed in ganglion cells from TRPM3-/- mice. Similarly, PS-stimulated currents that could be blocked by mefenamic acid were recorded from wild type retinal ganglion cells but were absent in ganglion cells from TRPM3-/- mice.
Highlights
The retina is a small neural network which converts light stimuli into parallel pathways of neural activity that are propagated to the brain
Complementary DNA fragments encoding TRPM3 were obtained from mouse retina by RTPCR, and a full-length TRPM3 cDNA was constructed by overlap extension (Fig. 1A)
Cells were loaded with the calcium indicator, Fura-2, and Ca2+ signals recorded by ratiometric imaging in response to perfusion with 50 μM Pregnelone Sulfate (PS), a TRPM3 agonist (Fig. 2A)
Summary
The retina is a small neural network which converts light stimuli into parallel pathways of neural activity that are propagated to the brain. The retina expresses TRP channels from each of the major families, including the classic TRPs (TRPCs), the vanilloid receptor TRPs (TRPVs), and the melastatin TRPs (TRPMs) [2]. TRPCs function as receptor-operated channels and are thought to activate calcium signaling pathways and modulate cellular excitability. Channels of the TRPV family are best known as heat-activated channels, including TRPV1, the well-characterized capsaicin receptor involved in thermal nociception [5]. TRPM3 channels are found in islet cells of the pancreas, where they are though to regulate insulin secretion [7], and were recently discovered in temperature-sensitive neurons of the dorsal root ganglia [8]. TRPM3 is expressed in testes and in human, but not mouse, kidneys [11], [12]
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