Contribution of Plasma Membrane Calcium ATPases to neuronal maladaptive responses: Focus on spinal nociceptive mechanisms and neurodegeneration

Plasma membrane calcium ATPases (PMCAs) are ion pumps that expel Ca²⁺ from cells and maintain Ca²⁺ homeostasis. Four isoforms and multiple splice variants play important and non-overlapping roles in cellular function and integrity and have been implicated in diseases including disorders of the central nervous system (CNS). In particular, one of these isoforms, PMCA2, is critical for spinal cord (SC) neuronal function. PMCA2 expression is decreased in SC neurons at onset of symptoms in animal models of multiple sclerosis. Decreased PMCA2 expression affects the function and viability of SC neurons, with motor neurons being the most vulnerable population. Recent studies have also shown that PMCA2 could be an important contributor to pain processing in the dorsal horn (DH) of the SC. Pain sensitivity was altered in female, but not male, PMCA2^+/− mice compared to PMCA2^+/+ littermates in a modality-dependent manner. Changes in pain responsiveness in the female PMCA2^+/− mice were paralleled by female-specific alterations in the expression of effectors, which have been implicated in the excitability of DH neurons, in mechanisms governing nociception and in the transmission of pain signals. Other PMCA isoforms and in particular, PMCA4, also contribute to the excitability of neurons in the dorsal root ganglia (DRG), which contain the first-order sensory neurons that convey nociceptive information from the periphery to the DH. These findings suggest that specific PMCA isoforms play specialized functions in neurons that mediate pain processing. Further investigations are necessary to unravel the precise contribution of PMCAs to mechanisms governing pathological pain in models of injury and disease.