The Interplay between cGMP and Calcium Signaling in Alzheimer’s Disease

Abstract

Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer’s disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca2+ signaling, e.g., causing changes in cGMP-mediated Ca2+ release from the intracellular stores as well as Ca2+-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca2+ signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer’s disease.

Gene Co-Expression Analysis of Multiple Brain Tissues Reveals Correlation of FAM222A Expression with Multiple Alzheimer’s Disease-Related Genes

“…4D ). Both ATP2A3 and ITPR1 were involved in the cGMP and calcium signaling pathway, which was reported to be deregulated in AD patients and mouse models [ 23 ]. CLEC2L was reported to be downregulated in the entorhinal and temporal lobe cortex in AD patients [ 24 ].…”

Advances in the Electrophysiological Recordings of Long-Term Potentiation

“…Recently, there have been increasing investigations of electrically stimulated LTP observed at inhibitory synapses in different brain areas, including the hippocampus, although most are observed at excitatory synapses previously [ 93 ]. Researchers have demonstrated that excitatory LTP provides a more effective detection, while iLTP maintains the temporal resolution of the neuronal network by using a whole-cell patch clamp [ 94 ]. It means that the excitatory LTP is dominant for short stimulation intervals due to significant increases in spike generation.…”

“…Ca 2+ /calmodulin regulates constitutive expression types of the NOS family [ 92 ], confirming a possible connection to LTP and iLTP induction. Meanwhile, behavioral studies show that the NO/cGMP plays a role in learning and memory [ 93 , 94 ] because NO donors, l-Arginine, or cGMP analogs enhanced memory, whereas NOS inhibitors or genetic deletion hampered various types of memory [ 93 ].…”

cGMP Signaling in the Neurovascular Unit—Implications for Retinal Ganglion Cell Survival in Glaucoma

“…The role of NO-cGMP signaling in RGCs appears to be multifaceted. In CNS neurons, NO-cGMP signaling is important in NVC, synaptic plasticity, and synaptic transmission [ 107 ]. GC1 is expressed in pre- and post-synaptic terminals and in neuronal soma and spines [ 107 , 108 ].…”

“…In CNS neurons, NO-cGMP signaling is important in NVC, synaptic plasticity, and synaptic transmission [ 107 ]. GC1 is expressed in pre- and post-synaptic terminals and in neuronal soma and spines [ 107 , 108 ]. GC1 is also evident in RGC soma in the retina [ 26 ].…”