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Review
. 2020 Feb 18;14(1):7.
doi: 10.1186/s40246-020-00258-4.

TRPM3_miR-204: a complex locus for eye development and disease

Alan Shiels  1
Affiliations
Review

TRPM3_miR-204: a complex locus for eye development and disease

Alan Shiels. Hum Genomics. .

Abstract

First discovered in a light-sensitive retinal mutant of Drosophila, the transient receptor potential (TRP) superfamily of non-selective cation channels serve as polymodal cellular sensors that participate in diverse physiological processes across the animal kingdom including the perception of light, temperature, pressure, and pain. TRPM3 belongs to the melastatin sub-family of TRP channels and has been shown to function as a spontaneous calcium channel, with permeability to other cations influenced by alternative splicing and/or non-canonical channel activity. Activators of TRPM3 channels include the neurosteroid pregnenolone sulfate, calmodulin, phosphoinositides, and heat, whereas inhibitors include certain drugs, plant-derived metabolites, and G-protein subunits. Activation of TRPM3 channels at the cell membrane elicits a signal transduction cascade of mitogen-activated kinases and stimulus response transcription factors. The mammalian TRPM3 gene hosts a non-coding microRNA gene specifying miR-204 that serves as both a tumor suppressor and a negative regulator of post-transcriptional gene expression during eye development in vertebrates. Ocular co-expression of TRPM3 and miR-204 is upregulated by the paired box 6 transcription factor (PAX6) and mutations in all three corresponding genes underlie inherited forms of eye disease in humans including early-onset cataract, retinal dystrophy, and coloboma. This review outlines the genomic and functional complexity of the TRPM3_miR-204 locus in mammalian eye development and disease.

Keywords: Eye development; Eye disease; MicroRNA; TRP channel.

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Conflict of interest statement

The author declares that he has no competing interests.

Figures

Fig. 1
Fig. 1
TRPM3_miR-204 gene organization and protein coding domains. Schematic of the human TRPM3 gene (TRPM3) coding for RefSeq transcript-variant 9 and channel-isoform k. The non-coding miR-204 gene (MIR204) is located in intron-9 of TRPM3. Exons are indicated by numbered boxes (1–30). Codon numbers are shown below each coding exon (exons 3, 9, 16, and 30 are skipped). ATG denotes alternative translation start-sites. Asterisk denotes translation stop-site. Mutations in TRPM3 (exon 4 and 29) and MIR204 (intron 9) underlying human eye disease are shown in red. The approximate locations of TRPM3 protein coding domains are indicated as follows. TRPM-start, consensus start of the N-terminal TRPM homology domain (~ 700 amino acids). CaM/S100A1/PI(4,5)P2, calmodulin, S100A1 Ca2+-binding protein, and phosphatidylinositol-4,5-biphosphate binding domains. CaM2–5, calmodulin binding domains 2–5. ICF, indispensable for channel function. S1-S4, transmembrane segments 1–4, S5-P-S6, canonical pore flanked by transmembrane segments 5 and 6. TRP1–2, TRP box/motif 1 and 2. C-C, coiled-coil domain. The insertion site of a gene-targeting construct (IRES-lacZ-neo) used to generate a null allele in the mouse TRPM3 gene (Trpm3) is located in exon 20
Fig. 2
Fig. 2
MiR-204 sequence, processing, and target sites. a Sequence alignment of human (MIR204) and mouse (Mir204) miR-204 genes. The 5p and 3p arms are shaded gray. The 7-nucleotide seed regions are underlined. Nucleotides critical for Drosha cleavage (C32, T92) and Dicer cleavage (T54, G71) are shown in blue and green, respectively. The n.37C > T transition underlying RDICC is shown in red. b Precursor (pre)miR-204 stem formation between the 5p and 3p arms. c Processed miR-204-5p aligned with binding sites in the mRNA 3′-untranslated regions (UTRs) of human TRPM3 and mouse Trpm3. Asterisks (*) denote identical nucleotides. Colons (:) denote base pairing. Dashes (−) denote sequence gaps
Fig. 3
Fig. 3
Amino acid alignment of human TRPM3 isoform-k (hK) and mouse TRPM3 isoform-w (mW). Partial amino acid alignments of mouse TRPM3 isoform-d (mD, alias mα2) and isoform-a (mA, alias mα1) are included. Bars denote identical amino acids. Colons denote similar amino acid changes. Single dots denote dissimilar amino acid changes. Dashes denote gaps. CaM1, first calmodulin binding-site in mD/mα2 (K41-P61, shaded gray). Gray-shaded bars denote protein domains as follows. TRPM-start, consensus start-motif of the ~ 700 amino acid TRPM domain. CaM2–5, calmodulin binding-sites 2–5 in hK, mW, and mD/mα2. An in silico CaM6 binding-site (P966-L987) overlapping S4 in mW is underlined. CaM/S100A1 and PI(4,5)P2 binding-sites in hK (A35-K124, H291-G382) are also underlined. Putative PH-like domains and PI(4,5)P2 binding-sites (K302-R311, K596-K611) in hK are shown in italics. ICF, indispensable for channel function domain (mD/α2), S1-S6, transmembrane α-helical segments, P-loop, canonical pore-forming loop, TRP1–2, TRP-domain containing TRP-box 1 (1127-WKFQR-1132) and TRP-box 2 (1144-LPPPL-1148), and C-C, coiled-coil domain (R1219-T1271). /\ indicates location of ‘long-pore’ region of mA/α1 that is absent in hK, mW, and mD/mα2. Alternative methionine translation start-sites (M1, M65, M154), cataract-associated mutations (p.I65M, p.R1470T), and functionally important amino-acids in the CaM/S100A1 binding-site (K45, R67, K71, R72), CaM2 binding-site (K198, K200, K205, K209), ICF domain (L516-Y525), S1 helix (Y976, Y780, Y783), S3 helix (E939), S4 helix (W980, R983, D986, G989), and P-loop region (E1055) are shown in red font. A synthetic-peptide (L1030-N1043) located in the third extracellular loop (P-loop) of hK used to raise a polyclonal antibody (TM3E3) is shaded gray. The C-terminal sequence of the truncated hTRPM3–1325 isoform (hS) is indicated. Asterisks denote translation stop-sites
Fig. 4
Fig. 4
Schematic summary of TRPM3 channel gating and signal transduction. Agonists PS or CIM0216 stimulate Ca2+ influx via the canonical central pore (S5-P-S6) of TRPM3 homomeric tetramers ({}), whereas, mefenamic acid acts as an antagonist. Membrane phosphoinositides (PIPs) enhance PS-activated TRPM3 Ca2+ influx. PS in combination with Clt, or CIM0216 by itself, can also stimulate Na+ influx via an alternative pore opening ([]), distinct from the canonical TRP-pore. TRPM3 and TRPM1 monomers can also form heteromeric channels. TRPM3 channels are also permeable to Zn2+ and Mg2+, whereas, Zn2+ inhibits TRPM1 channels. TRPM3-elevated intracellular Ca2+ phospho-activates cytoplasmic MAPK signal transducers ERK1/2 and JNK1/2 that in turn phospho-activate nuclear transcription factors AP-1, ELK1, and CREB. Phosphatases CaN and DUSP1 provide feed-back inhibition of TRPM3-dependent Ca2+ signaling by de-phosphorylation of transcription factor pELK1 and the MAPKs pERK2 and pJNK1/2, respectively
Fig. 5
Fig. 5
Schematic of PAX6 and TRPM3_MIR204 in human inherited eye disease
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