PTMs have been shown to influence transporter kinetics both

PTMs have been shown to influence transporter kinetics, both directly and indirectly (Xu & You, 2017). They do not just regulate the innate structure-function relationship driven by a transporter's global architecture, but rather are also able to regulate this relationship down to the resolution of the structural events occurring at a residue level. From this level, PTMs are able to modulate a transporter's function, expression, efficiency, structure, fate, interactions, and more. Additionally, the complexity of the response of PTM modulation is a function of the extent of modifications a transporter is able to accept and the availability of the environmental cues to signal for the post-translational event (Table 2) (Hunter, 2007; Kaneko et al., 2012; Walsh et al., 2005). This results in an exponential increase in specific “species” of a given transporter, referred to as proteoforms (Toby, Fornelli, & Kelleher, 2016), which can provide deeper mechanistic understanding in transporter biology. The consequence of PTM modulation has been investigated for a wide range of SLC and ABC transporters, including but not limited to those described in the sections below. The purpose of this review is to provide a broad overview of the roles of PTMs in regulating transporters in higher vertebrates and humans, and consequently is not intended to be a comprehensive list of all of the PTMs identified to-date. Consequently, a diverse set of examples was selected from the literature to support the overarching themes in the post-translational regulation of ABC and SLC transporters (Table 3).
Phosphorylation
Acetylation
Lipidic modifications
Ubiquitination
SUMOylation
Conclusions The fate of the transporter following a post-translational event also does not always lead to an extreme consequence, such as degradation. There is significant data for a variety of modifications involving transient effects. GLUT4 for instance is (de)-SUMOylated to rapidly respond to Lopinavir signals and translocate from intracellular pools to the cell surface. This occurs rapidly to adapt to the metabolic needs of the system. Additionally, post-translational signals can dictate the sub-membrane fate and trafficking of many transporters. This is critical in interpreting transporter expression, such that surface expression does not always equate to functional expression. An example of this is with the Na+/Ca2+ exchanger 1, NCX1 (SLC8A1), where palmitoylation is capable of shifting the SLC transporter into lipid raft domains. Similar observations have been seen with PKC-signaled fates for SLC transporters, and N-glycosylation of GLUT2. It important to recognize that there also seems to be a general bias in the literature for studying PTMs of transporters. While we tried to choose a diverse set of transporters for this review, generally from our observations a significant amount of the literature appears to focus on specific SLC neurotransporters, such as DAT and the ABC transporter, CFTR. While this yields impressive mechanistic insight into those particular transporters, there is limited information still to extrapolate roles for a specific PTM to a general transport regulatory mechanism. The extent in which PTMs regulate transporters is far from being fully appreciated, yet it cannot be expected that every proteoform will have a unique and clinically relevant phenotype. However, those that do must be considered not only in the context of human health but also in the context of the safety and efficacy of therapeutic interventions. While transporters play significant roles in the pharmacokinetics and pharmacodynamics of drugs, the capacity of drugs to modulate off-target signaling pathways is typically only recognized during development. The indirect implications of a pharmacological agent on the endogenous regulation of transporters may be significant in characterizing off-target effects. This is exemplified by the use of kinase inhibitors clinically. In the case of MDR, kinase inhibitors provide promise for increasing the availability of a therapeutic in a target tissue, yet we do not fully understand how this impacts transporters for endogenous substrates. In the case of OCTs and OATs, it suggests that these inhibitors affect transporters at a cellular level, but what the consequences are in vivo is less certain. Despite the need for understanding the risks, as more information accumulates regarding the consequence of modulating PTMs, transporter proteoforms may prove to be viable targets and/or biomarkers for a profound range of clinical manifestations.