Neurons are large, morphologically complex cells whose normal physiological function requires targeting of different voltage- and ligand-gated ion channels to specific subcellular locations. For example, voltage-gated calcium channels and neurotransmitter receptors must be clustered pre- and post-synaptically, respectively, to ensure the fidelity of synaptic transmission (Buonarati et al., 2019; Dolphin and Lee, 2020; Sanz-Clemente et al., 2013; Suh et al., 2018). In addition, voltage-gated sodium and potassium channels must be clustered at the axon initial segment (AIS) and, in myelinated axons, at or near nodes of Ranvier, to ensure correct initiation and propagation of action potentials (Catterall, 1981; Huang and Rasband, 2018; Leterrier, 2018; Lorincz and Nusser, 2008; Nelson and Jenkins, 2017; Waxman and Foster, 1980).

Several mechanisms ensure the appropriate targeting of neuronal ion channels and receptors. In particular, non-enzymatic scaffold proteins, particularly those containing PSD95/discs large/ZO-1 (PDZ) domains, directly bind the intracellular C-terminal tails of several families of receptors and channels and thereby control their trafficking to, and/or stability at, precise subcellular sites (Kim and Sheng, 2004). PDZ domains are subdivided into several classes with the two best known subclasses, Type-I and Type-II PDZ domains, binding C-terminal sequences ending in S/T-X-V (where X is any amino acid) and Φ-X-Φ (where Φ is a hydrophobic amino acid), respectively (Nourry et al., 2003).

A second mechanism to control receptor, ion channel, and scaffold protein interactions and targeting is dynamic post-translational modification. One post-translational modification whose importance in neurons is increasingly appreciated is the covalent addition of long-chain fatty acids to protein cysteine residues, a process called S-palmitoylation (or S-acylation, referred to here simply as palmitoylation) (Chamberlain and Shipston, 2015; Fukata and Fukata, 2010; Hallak et al., 1994; María-Eugenia and Van Der Goot, 2018; Smotrys and Linder, 2004). Palmitoylation plays key roles in neurons (Sanders et al., 2015), particularly at synapses where many scaffold proteins and ion channels and receptors are palmitoylated (Matt et al., 2019; Naumenko and Ponimaskin, 2018; Thomas and Huganir, 2013b).

We previously suggested that these two mechanisms might act in concert because a surprising number of palmitoyl acyltransferases (PATs) possess C-terminal sequences that are themselves predicted to bind PDZ domain proteins (Thomas and Hayashi, 2013a). However, almost all of these potential PDZ-binding PATs terminate in Type-II PDZ ligand (Φ-X-Φ) sequences and hence are unlikely to directly bind major Type-I PDZ domain proteins, several of which are important palmitoyl-proteins in neurons (Hung and Sheng, 2002; Kim and Sheng, 2004). The only PAT that contains a C-terminal Type-I PDZ ligand (S/T-X-V) is ZDHHC14 (Thomas and Hayashi, 2013a), a PAT whose neuronal roles and substrates are unknown. The lack of investigation of ZDHHC14 is perhaps surprising, given that this PAT is highly expressed in the hippocampus (Cembrowski et al., 2016; Zeisel et al., 2018) and may even be the most highly expressed PAT in this brain region (Cajigas et al., 2012). ZDHHC14 is also one of only four PATs intolerant to loss of function genetic mutations in humans (Lek et al., 2016). This latter finding suggests that role(s) of ZDHHC14 cannot be compensated for by other PATs, which might be explained by ZDHHC14’s unique predicted PDZ-binding ability.

Here, we identify the Type-I PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) family scaffold protein PSD93 (post-synaptic density 93/chapsyn 110/DLG2) (Kim et al., 1996) as a direct interactor and substrate of ZDHHC14. Like its close paralog, PSD95, PSD93 is a known palmitoyl-protein (El-Husseini et al., 2000b; Topinka and Bredt, 1998). However, while palmitoylation is well described to control PSD95 targeting to the post-synaptic membrane (Firestein et al., 2000), the role of PSD93 palmitoylation is less clear. We provide evidence that palmitoylation by ZDHHC14 targets PSD93 not to synapses, but to the AIS. Loss of ZDHHC14 also reduces palmitoylation and AIS targeting of Kv1 family potassium channels, whose clustering at the AIS was previously reported to be PSD93-dependent (Ogawa et al., 2008). Consistent with this model, and with the known role of Kv1 channels in constraining action potential firing (Yamada and Kuba, 2016), loss of ZDHHC14 reduces outward currents, which are likely mediated by voltage-dependent potassium channels, and also increases neuronal excitability. These findings have implications for our understanding of physiological regulation of neuronal excitability and how such regulation is impaired in conditions linked to hyper-excitation.

Precise control of ion channel and receptor subcellular localization is critical to regulate and adjust neuronal excitability. Palmitoylation is a key mechanism that allows precise and dynamic regulation of protein targeting during development and in response to neuronal input (Sanders et al., 2015). However, while roles of palmitoylation in regulating protein targeting at the synapse are reasonably well described (Brigidi et al., 2014; Firestein et al., 2000; Fukata and Fukata, 2010; Fukata et al., 2013; Hayashi et al., 2005; Hayashi et al., 2009), far less is known regarding the importance of palmitoylation at other sites involved in neuronal excitation. Here we identify ZDHHC14 as a key controller of palmitoylation and AIS targeting of PSD93 and Kv1 family channels. Loss of ZDHHC14 also profoundly increases neuronal excitability, a finding that could be explained by loss of Kv1 channels from the AIS. Clustering of Kv1 channels at the AIS is thus controlled by palmitoylation-dependent mechanisms reminiscent of those that govern targeting glutamate receptors to synapses (Firestein et al., 2000; Fukata et al., 2013; Hayashi et al., 2005; Hayashi et al., 2009; Thomas et al., 2012; Thomas and Huganir, 2013b). However, AIS targeting of Kv1 channels involves a distinct PDZ-domain protein and a different, largely unstudied PAT.

PSD93’s interaction with, and palmitoylation by, ZDHHC14 is dependent on ZDHHC14’s C-terminal PDZ ligand (Figure 1), suggesting that ZDHHC14 recognizes PSD93, and perhaps other substrates, in a PDZ ligand-dependent manner. This PDZ ligand-dependent mechanism of substrate recognition by a PAT was also reported for ZDHHC5 and ZDHHC8, which use their Type-II PDZ ligands to bind and palmitoylate the PDZ domain-containing protein GRIP1b (Thomas et al., 2012). While these are the only three PATs known to use this mechanism of substrate recognition, certain kinases also bind and phosphorylate PDZ domain-containing substrates in a manner dependent on the kinase’s PDZ ligand (Hasegawa et al., 1999; Sabio et al., 2004; Thomas et al., 2005).

Although the C-termini of Kv1.1, Kv1.2, and Kv1.4 are not predicted to bind ZDHHC14, they all terminate in Type-I PDZ ligands that (i) are critically important for their axonal targeting (Arnold and Clapham, 1999) and (ii) can directly bind PSD93 (Kim et al., 1995; Kim et al., 1996). Thus, it is possible that PSD93 is not only a direct ZDHHC14 substrate but also acts as a scaffold to allow ZDHHC14 to control palmitoylation and subcellular targeting of Kv1 channels. This possibility is further increased by our finding that ZDHHC14 binds PDZ domain 3 of PSD93 (Figure 1—figure supplement 2), while Kv1.4 binds PDZ domain 2 of PSD93 (originally described as an unidentified ‘Clone 5’ by Kim et al., 1995) and subsequently confirmed as PSD93/Chapsyn-110 by Kim et al., 1996. However, ZDHHC14 is not enriched at the AIS, but rather predominantly localizes to the Golgi (Figure 8A,B). These findings would support a model in which PSD93 acts as a scaffold for Kv1 channels and ZDHHC14 at the Golgi to allow ZDHHC14-dependent palmitoylation of Kv1 channels and their subsequent co-trafficking with PSD93 to the AIS. This mechanism is not unprecedented, as palmitoylation within the Golgi was reported to facilitate forward trafficking of the BK potassium channel (Tian et al., 2012).

ZDHHC14 loss significantly reduces palmitoylation of PSD93 and Kv1 channels (Figure 2, Figure 6) but does not eliminate palmitoylation of these proteins. Whether this residual palmitoylation is due to the presence of other PATs, incomplete Zdhhc14 knockdown, or both, is currently unknown. Assessing residual (non-ZDHHC14-dependent) palmitoylation of these proteins could potentially require developing reagents to knock-down multiple additional PATs. Some potential insight into this issue is provided by a recent report that the zebrafish ortholog of Kv1.1 could be palmitoylated by the PAT HIP14 (ZDHHC17) in cotransfected HEK293 cells, although palmitoylation of endogenous neuronal Kv1.1 by ZDHHC17/HIP14 was not assessed (Nelson et al., 2020). HIP14/ZDHHC17 might thus be a candidate to contribute to residual palmitoylation of Kv1.1 (as well as possibly other Kv1 channels). However, ZDHHC17 is less likely to mediate residual PSD93 palmitoylation because this PAT lacks a Type-I PDZ ligand and loss of ZDHHC17 does not affect PSD93 palmitoylation in mice (Wan et al., 2013). While we cannot rule out roles for ZDHHC17/HIP14 and/or other PATs, our findings suggest that PSD93 and Kv1 palmitoylation is dominantly controlled by ZDHHC14 in hippocampal neurons.

The temporally similar developmental upregulation of ZDHHC14, PSD93, and Kv1 channel protein levels (Figure 5) is striking, but such a biochemical analysis cannot address the subcellular location(s) to which these proteins localize as their levels increase. However, a prior study reported, albeit non-quantitatively, that Kv1.2 is first detectably enriched at the AIS of cultured hippocampal neurons at a very similar timepoint (DIV13) to when we observe marked upregulation of total Kv1.2 protein levels (DIV12; Figure 5; Sánchez-Ponce et al., 2012). This finding strengthens the possibility that Kv1.2 upregulation coincides with and/or results in its AIS targeting. We nonetheless appreciate that more in-depth analyses, potentially involving laser-capture dissection of sufficient individual AIS’s to run immunoblots and/or comprehensive, semi-quantitative immunocytochemical experiments at individual AIS’s, would be required to further test this hypothesis.

Intriguing, additional support for a shared function of ZDHHC14, PSD93, and Kv1 channels in AIS regulation emerges from examining the evolutionary conservation of ZDHHC14, PSD93, and the AIS itself. Sodium channel clustering in proximal axons is first observed immunohistologically in vertebrates, coincident with the evolution of AIS-anchoring domains in these channels (Kole and Stuart, 2012). Similarly, N-terminal palmitoylation sites are only present in vertebrate orthologs of PSD93 and are absent in the fruit fly PSD93 ortholog Discs Large (DLG) (Thomas and Hayashi, 2013a). Lastly, ZDHHC14’s PDZ ligand, which greatly increases ZDHHC14’s ability to palmitoylate PSD93 (Figure 1), is first observed in simple chordates (Ciona intestinalis) and vertebrates (Figure 1—figure supplement 1). In contrast, palmitoyl-sites and PDZ ligands in Kv1 channels are more evolutionarily ancient (Figure 5—figure supplement 1B). However, the ability of ZDHHC14 to palmitoylate PSD93, and for palmitoyl-PSD93 to act as a scaffold to cluster Kv1 channels at the AIS, appear to have evolved with the appearance of the AIS itself as nervous systems became more complex.

Several lines of evidence are consistent with direct loss of Kv1-type voltage-gated potassium channels accounting for the increased excitability of Zdhhc14 knockdown neurons. First, ZDHHC14 loss decreases outward currents, a phenotype most readily accounted for by reduced number and/or function of voltage-gated potassium channels (Figure 9; Dodson et al., 2002). ZDHHC14 loss also reduces AIS localization of multiple Kv1 family channels, assessed immunocytochemically (Figure 7). Moreover, Kv1-type channels activate at subthreshold membrane potentials and counteract voltage-gated sodium channel (Nav) currents, thereby dampening action potential firing and reducing neuronal excitability (Clark et al., 2009; Dodson et al., 2002; Yamada and Kuba, 2016). The decrease in outward currents and increase in excitability seen after ZDHHC14 loss are thus both consistent with a reduction in Kv1 channel number and/or function.

Specific features of APs in Zdhhc14 knockdown neurons are also consistent with reduced Kv1 channel number and/or function. For example, Kv1-type channels are known to regulate AP firing by suppressing generation of, as well as shortening, action potentials (Yamada and Kuba, 2016) so Kv1 channel loss at the AIS could account for the decreases in latency to the first action potential, rheobase, and rate of action potential repolarization seen in Zdhhc14 knockdown neurons (Figure 9D,E,G; Table 1). Indeed, the slight but significant AP broadening that we observed in Zdhhc14 knockdown neurons (half-width; Table 1) was also seen following acute block of Kv1 channels (Guan et al., 2018; Kole et al., 2007).

We are nonetheless aware that other factors may also influence excitability in Zdhhc14 knockdown neurons. For example, while the slightly increased resting membrane potential is also consistent with loss of Kv1 channels, we cannot exclude roles for other voltage-gated potassium channels in this increase. An increased resting membrane potential could also inactivate a subset of voltage- gated sodium channels, which might in turn account for the decreased peak AP amplitude and rate of AP rise seen with Zdhhc14 knockdown (Table 1).

Another change seen after ZDHHC14 loss is the shortening of the AIS itself (Figure 3D), previously reported to be a compensatory response to increased neuronal excitability (Dumitrescu et al., 2016; Grubb et al., 2011; Grubb and Burrone, 2010). Like the increased membrane potential, this decreased AIS length could thus be a secondary consequence of Kv1 loss after Zdhhc14 knockdown but could also be due to other changes. In summary, several aspects of the excitability changes in Zdhhc14 knockdown neurons are consistent with a direct loss of Kv1 channels, but we recognize that other changes may be downstream secondary consequence of such loss, or may be due to altered regulation of other voltage-dependent channels and/or AIS structural proteins.

We also recognize that mutating the palmitoyl-cysteines of the PSD93β isoform reduces AIS localization of PSD93 (Figure 4) to a lesser extent than is seen following loss of ZDHHC14 itself (Figure 3). These findings suggest that additional ZDHHC14 substrate(s) may also contribute to AIS localization of PSD93. Kv1 channels themselves, which PSD93 directly binds and which are robustly palmitoylated in a ZDHHC14-dependent manner (Figure 6), could potentially play such a role. It is especially intriguing that many other AIS-localized ion channels, scaffolds, and cell adhesion molecules are either known or predicted to be palmitoylated (Blanc et al., 2015; He et al., 2012; Nelson and Jenkins, 2017; Pei et al., 2016). It would be important to determine in the future the extent to which ZDHHC14 loss impairs palmitoylation of these proteins, and how any such additional changes in palmitoylation might affect not just PSD93 localization, but also the broader structure and/or function of the AIS.

Given that ZDHHC14 may regulate other palmitoyl-proteins, it is theoretically possible that signals in our biochemical and/or immunocytochemical experiments could represent heteromultimers of PSD93 and its paralogous palmitoyl-protein PSD95, which were reported in transfected non-neuronal cells (Kim et al., 1996). However, subsequent studies of endogenous proteins from brain tissue suggested that although both PSD95 and PSD93 are found in multimeric complexes, endogenous PSD93/PSD95 heteromultimers were not detected (i.e. the endogenous multimeric complexes consist of homomeric PSD95 or PSD93, but not both) (Hsueh et al., 1997). Moreover, any potential heteromultimerization would not be an issue for our ABE assays, which assess denatured proteins that run as monomers on SDS-PAGE (Figure 1, Figure 2). We also note that our PSD93 antibody is validated using knockout tissue by the supplier. This antibody might still theoretically detect PSD95 in immunocytochemical experiments, but a prior study reported that PSD95 (detected with another widely used monoclonal antibody, which is itself validated using knockout tissue) is undetectable at the AIS, whereas PSD93 is AIS-localized (Ogawa et al., 2008). Importantly, we used the same PSD93 antibody, and a very similar fixation protocol, to the work of Ogawa et al. We would thus expect that antibodies against PSD93 (and also PSD95, if we were to use them) would show similar specificity in our experiments. Together, these findings suggest that we do not detect PSD93/PSD95 heteromultimers in either biochemical or immunocytochemical assays.

We also note that the effect of ZDHHC14 loss on neuronal excitability is more dramatic than the effect on AIS targeting of any individual Kv1 channel (Figure 7 versus 9). One possible explanation for this finding is that palmitoylation not only regulates channel targeting to the AIS but also regulates Kv1 channel electrophysiological responses. Indeed, palmitoylation was previously shown to modulate voltage-sensing of Kv1.1 expressed in Sf9 cells and loss of Kv1.1 palmitoylation decreased current amplitude (Gubitosi-Klug et al., 2005). Importantly, though, another intriguing possibility is that ZDHHC14 is a master regulator of multiple AIS ion channels and/or scaffold proteins and that impaired localization and/or function of these additional ZDHHC14 substrates further impacts neuronal excitability.

While we have focused this study on physiological neuronal regulation, our findings also have implications for our understanding of how neuronal excitability is altered in conditions such as epilepsy. Indeed, mutations in multiple Kv1 channel genes and copy number variations of the Dlg2 gene (which codes for PSD93) are associated with multiple neurological conditions characterized by neuronal hyperexcitability, including epilepsy, myokemia, episodic ataxia, schizophrenia, autism spectrum disorder, and intellectual disability (Cuscó et al., 2009; Eunson et al., 2000; Felix, 2000; Gao et al., 2018; Reggiani et al., 2017; Walsh et al., 2008). It is an intriguing possibility that dysregulated palmitoylation of PSD93 and/or Kv1 channels contributes to the pathogenesis of such conditions. In contrast, ZDHHC14 has not, thus far, been associated with any neuropathological condition. However, ZDHHC14 is one of only four PATs intolerant to loss of function mutations in humans, suggesting that it may be an essential gene (Lek et al., 2016). While it is possible that roles of ZDHHC14 in non-neuronal tissues underlie this requirement, it is again intriguing that ZDHHC14’s potential action as a master regulator of AIS structure and function could account for its indispensability.

In summary, our findings that palmitoylation of PSD93 by ZDHHC14 is important for regulating targeting of voltage-gated ion channels to the AIS and for neuronal excitability, provide key insights into multiple outstanding questions. To our knowledge, these findings identify the first substrates of ZDHHC14 in any system and reveal, for the first time, a role for PSD93 palmitoylation in neurons, a question that has remained unanswered for two decades. We also demonstrate that Kv1 family voltage-gated potassium channels are endogenously palmitoylated in neurons and provide additional mechanistic insight into the regulation of their AIS targeting and physiology. These findings have important implications for our understanding of physiological regulation of neuronal excitability and its dysfunction in epilepsy and/or other conditions marked by hyper-excitation.

All data generated during this study are included in the manuscript and supporting files. Source data files have been provided for all figures in the source data excel file.

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Author details

1. Shaun S Sanders

   Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Present address

   Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review and editing

   For correspondence

   ssande03@uoguelph.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9661-141X

2. Luiselys M Hernandez

   Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Heun Soh

   Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Santi Karnam

   Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

5. Randall S Walikonis

   Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

   Contribution

   Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Anastasios V Tzingounis

   Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

   Contribution

   Data curation, Formal analysis, Supervision, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4605-3437

7. Gareth M Thomas

   1. Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, United States
   2. Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   gareth.thomas@temple.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3183-8431

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