The SERCA2: A Gatekeeper of Neuronal Calcium Homeostasis in the Brain

Abstract

Calcium (Ca²⁺) ions are prominent cell signaling regulators that carry information for a variety of cellular processes and are critical for neuronal survival and function. Furthermore, Ca²⁺ acts as a prominent second messenger that modulates divergent intracellular cascades in the nerve cells. Therefore, nerve cells have developed intricate Ca²⁺ signaling pathways to couple the Ca²⁺ signal to their biochemical machinery. Notably, intracellular Ca²⁺ homeostasis greatly relies on the rapid redistribution of Ca²⁺ ions into the diverse subcellular organelles which serve as Ca²⁺ stores, including the endoplasmic reticulum (ER). It is well established that Ca²⁺ released into the neuronal cytoplasm is pumped back into the ER by the sarco-/ER Ca²⁺ ATPase 2 (SERCA2), a P-type ion-motive ATPase that resides on the ER membrane. Even though the SERCA2 is constitutively expressed in nerve cells, its precise role in brain physiology and pathophysiology is not well-characterized. Intriguingly, SERCA2-dependent Ca²⁺ dysregulation has been implicated in several disorders that affect cognitive function, including Darier's disease, schizophrenia, Alzheimer's disease, and cerebral ischemia. The current review summarizes knowledge on the expression pattern of the different SERCA2 isoforms in the nervous system, and further discusses evidence of SERCA2 dysregulation in various neuropsychiatric disorders. To the best of our knowledge, this is the first literature review that specifically highlights the critical role of the SERCA2 in the brain. Advancing knowledge on the role of SERCA2 in maintaining neuronal Ca²⁺ homeostasis may ultimately lead to the development of safer and more effective pharmacotherapies to combat debilitating neuropsychiatric disorders.

Keywords: Brain; Calcium; Darier’s disease; Neuron; SERCA2.

Fig. 1

Neuronal Ca²⁺-handling: Ca²⁺ influx in neurons is mediated by calcium-permeable AMPA and NMDA glutamate receptors, nicotinic acetylcholine receptors (nAChR), transient receptor potential type C (TRPC) channels, and voltage-gated calcium channels (VGCC). Ca²⁺ ions enter into the intracellular Ca²⁺ stores (i.e., mitochondria and the ER) by the mitochondrial uniporter and the sarco-/endoplasmic reticulum calcium ATPase (SERCA). Ca²⁺ release from internal stores is mediated by inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) that reside on the ER membrane. Ca²⁺ efflux to the extracellular fluid is mediated by the sodium–calcium exchanger (NCX) and the plasma membrane calcium ATPase (PMCA). Ca²⁺-binding proteins serve as Ca²⁺ ion sensors, buffering the cytosolic levels of Ca²⁺; arrows show the direction of Ca²⁺ ion movement

Fig. 2

SERCA2 structure: SERCA2 is a P-type Ca²⁺ ATPase that resides on the SR/ER membrane, protruding into the cytosol. It consists of 10 transmembrane helices (M1–10), a cytosolic stalk domain, and three main domains, A, P, and N. The A domain is the actuator domain, the N domain is responsible for nucleotide-binding, and the P domain accounts for the phosphorylation domain of the enzyme. All SERCA2 isoforms present a very well-conserved structure, but differ in the length of the C-terminal, with SERCA2b isoform having the most extended carboxyl terminal, potentially forming an eleventh transmembrane domain (M11)

Fig. 3

The primary structure of the carboxyl termini of the SERCA2a-d isoforms: The structure of the SERCA2 isoforms is highly conserved but their carboxyl termini differ (3′-end). Slashes mark the splice sites