Mini ReviewProperties and functions of TRPM1 channels in the dendritic tips of retinal ON-bipolar cells
Introduction
In the mammalian retina five different neuronal cell types are arranged in different layers and the cell bodies of retinal bipolar cells are located in the so-called inner nuclear layer, which is the middle one of three retinal layers predominantly containing cell bodies. According to their anatomical position, bipolar cells connect with their dendrites to the classical photoreceptor cells, rods and cones, while the axonal terminals make contacts with amacrine and ganglion cells. In mammals, 13 distinct types of bipolar cells have been described that morphologically and functionally fall into two separate major groups, OFF- and ON-bipolar cells (for review see Euler et al., 2014). Within the photoreceptor cells, variations in incident light intensity are transduced into an electric signal, which in turn modulates the glutamate release from the presynaptic terminals of photoreceptor cells. An increase in light intensity leads to hyperpolarization of rods and cones and hence to reduced presynaptic glutamate release, to which bipolar cells then react. OFF-bipolar cells hyperpolarize to glutamate reduction, while ON-bipolar cells depolarize (reviewed in Snellman et al., 2008, Euler et al., 2014). Importantly, these physiological subtypes of bipolar cells can also be distinguished anatomically, as ON-bipolar cells have longer axons and terminate in deeper sub-stratifications of the inner plexiform layer compared to OFF-bipolar cells (Euler et al., 2014, Wässle, 2004). A special subtype of ON-bipolar cells is formed by the so-called rod bipolar cells, which terminate in the deepest sublayer of the inner plexiform layer and are essential for the efficient transmission of dim light signals (Wässle, 2004, Wässle et al., 1991). Each rod bipolar cell receives input from numerous rods and, unlike other bipolar cells, makes contacts only with AII amacrine cells. These cells then relay the signals to cone bipolar cells via gap junctions and glycinergic synapses. Only the cone bipolar cells connect directly to the retinal output neurons, the ganglion cells. The importance of this pathway for vision at low light intensities is demonstrated by the fact that the failure of this pathway results in night blindness. Mutations in a heterogeneous group of proteins cause congenital night blindness, but all these mutations affect the function of either rods or rod bipolar cells (Zeitz et al., 2015). Since rod bipolar cells are by far the most abundant bipolar cells in the retinae of most mammalian species, their electrical activity can be measured even at the surface of the cornea as the b-wave in electroretinogram (ERG) recordings of the dark-adapted eye. A reduction or absence of the b-wave is indicative of severe malfunction of the dim-light pathway and is very useful in assessing the function of rod bipolar cells, both experimentally and clinically (Robson and Frishman, 1998).
Horses with the “Appaloosa spotting” coat pattern have a high propensity to be affected by congenital stationary night blindness (CSNB). Initially, it was found that the locus responsible for this coat color pattern in horses contained, among others, the gene encoding for the cation channel TRPM1 (Bellone et al., 2006). Subsequent work showed that the causative mutation indeed affects TRPM1 expression, because an insertion of a long terminal repeat of an endogenous retrovirus into exon 1 of the TRPM1 gene disrupts gene transcription resulting in complete loss of TRPM1 protein (Bellone et al., 2008, Bellone et al., 2010, Bellone et al., 2013).
From developmental studies, TRPM1 was known to be expressed in the inner nuclear layer of murine retina (Kim et al., 2008a, Kim et al., 2008b). Several groups independently confirmed that in the retina of rodents and other species, TRPM1 is selectively and strongly expressed in the inner nuclear layer, specifically in bipolar cells (Gilliam and Wensel, 2011, Koike et al., 2010, Morgans et al., 2009). Importantly, in electrophysiological recordings from TRPM1-deficient ON-bipolar cells the characteristic glutamate-sensitive electrical response is strongly reduced or entirely absent (Koike et al., 2010, Morgans et al., 2009), while the response from OFF-bipolar cells appears largely unaffected (Koike et al., 2010). Consequently, TRPM1-deficiency in mice also results in suppression of the b-wave in ERG recordings, strongly indicating that these mice are nightblind (Koike et al., 2007, Koike et al., 2010, Morgans et al., 2009, Shen et al., 2009).
In humans, the search for genetic abnormalities in patients with CSNB similarly revealed that mutations in the TRPM1 gene are causative for CSNB (Audo et al., 2009, van Genderen et al., 2009, Li et al., 2009, Nakamura et al., 2010), a finding that has been confirmed several times in different populations (Bijveld et al., 2013, Malaichamy et al., 2014, Masurel-Paulet et al., 2014, Prasun et al., 2014). Mutations in TRPM1 are now thought to be the leading cause for the complete form of CSNB, also called CSNB1 (Zeitz et al., 2015). Complete CSNB is a subtype of night blindness characterized by stable (stationary) disease symptoms and a complete absence of the ERG b-wave (but not the a-wave, which originates from rod photoreceptors). Like TRPM1, the other mutations causing complete CSNB occur all in genes expressed in ON-bipolar cells (Zeitz et al., 2015).
Before TRPM1 expression in the retina was identified, this protein had been detected in melanocytes and melanoma cancer cells (Duncan et al., 1998, Duncan et al., 2001, Oancea et al., 2009). In melanomas, absence of TRPM1 expression was found to correlate with stronger invasiveness of metastases and poorer patient outcome, leading to the use of TRPM1 as a clinical prognostic marker (Carlson et al., 2005, Duncan et al., 2001, Erickson et al., 2009). This was also the reason why TRPM1 first was named “melastatin”, which is still reflected in the letter “M” of the TRPM subfamily of ion channels. While nowadays the anti-proliferative and anti-metastatic properties of TRPM1 expression are attributed entirely to the co-expressed, intronic miRNA-211 (Levy et al., 2010), it is a pertinent observation that some melanoma patients develop melanoma-associated retinopathy. One symptom of melanoma-associated retinopathy is night blindness, with a severe reduction of the ERG b-wave. The serum of some melanoma-associated retinopathy patients contains autoantibodies reactive against TRPM1 proteins of retinal bipolar cells (Dhingra et al., 2011, Kondo et al., 2011, Wang et al., 2012). Furthermore, the injection of patient serum containing such anti-TRPM1 antibodies into the vitreal body of mice causes the suppression of the retinal b-wave, thereby providing strong evidence that these anti-TRPM1 antibodies are causing the symptoms of night blindness (Ueno et al., 2013, Xiong et al., 2013). Clinically, these findings have already proven useful, as the deterioration of low light vision in conjunction with the presence of auto-antibodies against TRPM1 can be instrumental in the identification and subsequent treatment of an otherwise occult melanoma (Dalal et al., 2013, Morita et al., 2014) or other cancers (Ueno et al., 2014). On a mechanistic level, these findings provide very strong evidence that functional TRPM1 proteins are necessary for the correct response of ON-bipolar cells to glutamate and that dysfunctional TRPM1 proteins cause night blindness.
Section snippets
Subcellular localization of TRPM1 proteins in bipolar cells
TRPM1 immunoreactivity is present in various compartments of bipolar cells. Most investigators found TRPM1 immunoreactivity in the cell somata of the inner nuclear layer, in presynaptic structures of the inner plexiform layer and a punctate-like staining of dendritic tips in the outer plexiform layer (Klooster et al., 2011, Koike et al., 2010, Križaj et al., 2010, Morgans et al., 2009). The function of TRPM1 proteins in the soma and the inner plexiform layer is entirely unknown, and therefore,
Biophysical, pharmacological and structural properties of TRPM1
It was a surprising finding that the vanilloid capsaicin, in higher concentrations, activates the transduction channel of mouse ON-bipolar cells (Shen et al., 2009), because this substance is rather known for its agonistic action on TRPV1 channels (Caterina et al., 1997). However, it was convincingly demonstrated with the use of TRPV1-deficient mice that the effect of capsaicin on ON-bipolar cells is independent of TRPV1. Similar data were obtained for anandamide, which however seems to be a
Conclusion and outlook
The discovery of TRPM1 as the long sought-after ion channel crucial for the signal transduction of ON-bipolar cells (Koike et al., 2010, Morgans et al., 2009) has been a major break-through that has enabled a host of following studies providing detailed knowledge about the composition and functional properties of this signaling pathway crucial for vision at low light intensities. The available data clearly indicate that TRPM1 proteins in the dendritic tips of ON-bipolar cells are embedded in a
Acknowledgements
Raissa Enzeroth and Sandra Plant provided excellent technical support. We thank Christian Goecke and Dr. Sandeep Dembla for critical reading of the manuscript. The work from the author's laboratory was supported by the DFG (SFB 593 TP A16).
References (115)
- et al.
Oligomeric state of purified transient receptor potential melastatin-1 (TRPM1), a protein essential for dim light vision
J. Biol. Chem.
(2014) - et al.
Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness
Am. J. Hum. Genet.
(2012) - et al.
TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness
Am. J. Hum. Genet.
(2009) - et al.
Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness
Ophthalmology
(2013) - et al.
Molecular diagnostics in melanoma
J. Am. Acad. Dermatol.
(2005) - et al.
Requirement for the PDZ domain protein. INAD, for localization of the TRP store-operated channel to a signaling complex
Neuron
(1997) - et al.
Diagnosis of occult melanoma using transient receptor potential melastatin 1 (TRPM1) autoantibody testing: a novel approach
Ophthalmology
(2013) - et al.
TRPM1 (Melastatin-1/MLSN1) mRNA expression in Spitz nevi and nodular melanomas
Mod. Pathol.
(2009) - et al.
Mutations in TRPM1 are a common cause of complete congenital stationary night blindness
Am. J. Hum. Genet.
(2009) - et al.
TRP channel gene expression in the mouse retina
Vision Res.
(2011)