Interactions with PDZ proteins diversify voltage‐gated calcium channel signaling

Abstract

Voltage‐gated Ca2+ (CaV) channels are crucial for neuronal excitability and synaptic transmission upon depolarization. Their properties in vivo are modulated by their interaction with a variety of scaffolding proteins. Such interactions can influence the function and localization of CaV channels, as well as their coupling to intracellular second messengers and regulatory pathways, thus amplifying their signaling potential. Among these scaffolding proteins, a subset of PDZ (postsynaptic density‐95, Drosophila discs‐large, and zona occludens)‐domain containing proteins play diverse roles in modulating CaV channel properties. At the presynaptic terminal, PDZ proteins enrich CaV channels in the active zone, enabling neurotransmitter release by maintaining a tight and vital link between channels and vesicles. In the postsynaptic density, these interactions are essential in regulating dendritic spine morphology and postsynaptic signaling cascades. In this review, we highlight the studies that demonstrate dynamic regulations of neuronal CaV channels by PDZ proteins. We discuss the role of PDZ proteins in controlling channel activity, regulating channel cell surface density, and influencing channel‐mediated downstream signaling events. We highlight the importance of PDZ protein regulations of CaV channels and evaluate the link between this regulatory effect and human disease.

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

“…An interesting feature of Ca v 3.2 is the existence of a PDZ-binding domain in its cytoplasmic C-terminus 116 . PDZ proteins might control calcium channels activity, regulate their plasma membrane density and influence downstream signalling pathways 117 . Several PDZ scaffolding proteins are found at the post-synaptic NMJ, including the neuronal nitric oxide synthetase (nNOS) and α-syntrophin 118 , 119 , MAGI-1c 120 and PDZ domain containing RING finger 3 (PDZRN3) 121 .…”

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“…HCN is typically associated with hyperpolarization and can lead to hyperexcitability when mutations disrupt its normal function [ 87 ]. The CaV channel, on the other hand, leads to various depolarization and intracellular activity variations when it undergoes mutations affecting its normal function [ 88 ]. The impaired ability of NKCC1/KCC2 cotransporters to maintain intracellular low Cl - has been found on the condition that the expression ratio of NKCC1 surpasses that of KCC2, resulting in the accumulation of biophysical Cl - currents within the cells, ultimately leading to pathological hyperexcitability [ 89 ].…”

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