Review TRPM3 in Brain (Patho)Physiology, 2021, Held and Toth

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https://www.frontiersin.org/journal...ology/articles/10.3389/fcell.2021.635659/full
open access

Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. This regulated ion permeation results in different electrical and chemical signals that are necessary to maintain physiological excitatory and inhibitory processes in the brain. Therefore, it is no surprise that disturbances in the functions of cerebral ion channels can result in a plethora of neurological disorders, which present a tremendous health care burden for our current society. The identification of ion channel-related brain disorders also fuel the research into the roles of ion channel proteins in various brain states.

In the last decade, mounting evidence has been collected that indicates a pivotal role for transient receptor potential (TRP) ion channels in the development and various physiological functions of the central nervous system. For instance, TRP channels modulate neurite growth, synaptic plasticity and integration, and are required for neuronal survival. Moreover, TRP channels are involved in numerous neurological disorders.

TRPM3 belongs to the melastatin subfamily of TRP channels and represents a non-selective cation channel that can be activated by several different stimuli, including the neurosteroid pregnenolone sulfate, osmotic pressures and heat. The channel is best known as a peripheral nociceptive ion channel that participates in heat sensation. However, recent research identifies TRPM3 as an emerging new player in the brain. In this review, we summarize the available data regarding the roles of TRPM3 in the brain, and correlate these data with the neuropathological processes in which this ion channel may be involved.
 
the Trpm3 gene appears to encode the highest number of channel isoforms reported within the TRP family...
The different isoforms arise from alternative splicing at the N terminal part of the channel and from alternative splicing of exons spread all over the gene...
several splice variants exist in humans, labeled as TRPM3a-f following their relative abundance (Lee et al., 2003). Even more transcript variants and predicted protein sequences are deposited in the public NCBI reference sequence (RefSeq) database (Shiels, 2020)...
However, most of the reported isoforms are not yet functionally characterized and their roles are largely unknown. Whether they form functional cation channels seems to depend on a specific region indispensable for channel f unctions (ICFR), which was identified to be essential for the channel formation. Isoforms lacking ICFR, like TRPM3α7, do not form functional ion channels, probably due to a disturbed tetrameric channel complex formation and a decreased plasma membrane expression. Therefore, when co-expressed with the functional TRPM3α2, TRPM3α7 acts as a dominant negative regulator of the channel activity (Frühwald et al., 2012). Although TRPM3α7 transcripts were detected and estimated to form about 15% of the total TRPM3 transcripts in the brain (Frühwald et al., 2012), its impact on brain-specific function is yet to be discovered...
Summary of above - there are a lot of different forms of TRPM3, some don't even appear to work as ion channels. We don't yet know the functions of each form.

In addition to differences in selectivity, there are also marked differences in the pharmacological properties of the short and long pore loop variants. For instance, the long pore loop variant TRPM3α1 is insensitive to pregnenolone sulfate (PregS), a well-characterized agonist of the short pore loop variants TRPM3α2-6, and the isoforms show different sensitivities to several other agonists and antagonists, as well
 
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