Critical functions of the membrane-associated periodic skeleton

How does MPS contribute to axonal structure and membrane function?

Neuronal axons are relatively long projections between the cell body and axon terminal that function as a corridor that allows for communication and transportation of cargo anterogradely and retrogradely. Based on its structural composition, the MPS was hypothesized to serve as a scaffold to provide mechanical stability in axons as well as help with membrane organization and compartmentalization^{(reviewed in 10)}. These theories are supported by several studies, including recent reports showing that the MPS restricts endocytosis in proximal axons¹¹, controls axon plasma membrane stability¹², and directs axon diameter^13,14. The study on MPS regulating axonal endocytosis was particularly interesting as the group found that clathrin-coated pits form on membrane patches that were devoid of spectrin mesh¹⁵. Furthermore, enhancing neuronal activity or disrupting the MPS enhanced endocytosis of the clathrin-coated pit formations¹¹.

How are receptors organized within the MPS/membrane interface?

Early studies on the MPS in neurons showed that it distributed transmembrane proteins like adhesion molecules and ion channels into periodic distributions along axons^1,16. How receptor tyrosine kinases (RTKs) are spatially organized on the neuronal surface was not well understood; thus, the Zhuang lab investigated whether MPS may also play a role in RTK organization in neurons. They found that the cannabinoid type 1 GPCR receptor and the neural cell adhesion molecule were recruited to the MPS along with RTKs in response to extracellular stimuli¹⁷. This colocalization led to RTK activation and downstream ERK signaling. Interestingly, they also showed that ERK signaling activated calpain-dependent MPS degradation as a feedback mechanism to suppress sustained signaling¹⁷. Recently, this signaling mechanism was developed into a chemically inducible system to study RTK activation, where a primary readout is ERK-dependent disassembly of the MPS¹⁸.

Can calcium signaling modulate MPS dynamic changes?

A critical property of actin is its dynamicity, which allows for the rapid production or destruction of actin structures to control cellular processes. This dynamic ability of actin is particularly important in neurons, which have both long-term, highly stable cellular structures and active remodeling structures. As discussed above, the MPS is primarily thought to provide mechanical support to the axon, implying that it may be a very stable actin structure. Conversely, the MPS studies on neurodegeneration and RTK signaling discussed above suggest that it can disassemble in response to stimuli, thus demonstrating dynamic properties. A recent study by Heller et al. showed that the MPS is actually highly dynamic and is constitutively remodeled by calcium signaling in neuronal cells²³. Using lattice structured illumination microscopy (SIM), the group found that MPS remodeling driven by calcium signaling resulted in spectrin degradation by calpain and PKC-mediated adducin phosphorylation²³. This is quite distinct from another recent study that showed that F-actin remodeling is highly active during the early development of the axonal MPS, but is less active in mature MPS (preprint). While there is still much to understand about MPS dynamics, it does appear that it has the capacity to undergo dynamic changes in response to multiple different types of stimuli.

Summary and future directions of discovery

Detection of these specialized MPS structures has boosted our understanding of the role that actin plays in the axons of neurons to regulate its structure, receptor signaling, and overall health of these specialized cells. Moreover, several other functions of the MPS have also been identified, including organizing membrane proteins, mechanosensation, neuronal excitability, microtubule crosstalk, and ion channel distribution^{(reviewed in 9, 19)}. Its importance in neurobiology is further supported by reports showing that several neurological diseases are linked to hereditary mutations of key MPS component proteins²⁴, and genetic disruption of the MPS in mice leads to neurological impairment^{25, 26}.Collectively, it is clear that the MPS is a critical actin structure that has a profound effect on neuronal health and function and may someday be a potential target to treat neurodegenerative diseases.

References

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