The role of soluble adenylyl cyclase in neurite outgrowth

Abstract

Axon regeneration in the mature central nervous system is limited by extrinsic inhibitory signals and a postnatal decline in neurons' intrinsic growth capacity. Neuronal levels of the second messenger cAMP are important in regulating both intrinsic growth capacity and neurons' responses to extrinsic factors. Approaches which increase intracellular cAMP in neurons enhance neurite outgrowth and facilitate regeneration after injury. Thus, understanding the factors which affect cAMP in neurons is of potential therapeutic importance. Recently, soluble adenylyl cyclase (sAC, ADCY10), the ubiquitous, non-transmembrane adenylyl cyclase, was found to play a key role in neuronal survival and axon growth. sAC is activated by bicarbonate and cations and may translate physiologic signals from metabolism and electrical activity into a neuron's decision to survive or regenerate. Here we critically review the literature surrounding sAC and cAMP signaling in neurons to further elucidate the potential role of sAC signaling in neurite outgrowth and regeneration. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.

Keywords: Axon growth; Optic nerve; Regeneration; Retinal ganglion cell.

Figure 1. sAC associates with mitochondria and responds to decreasing pH via bicarbonate activation

Increases in carbon dioxide (CO₂) resulting from metabolic energy production results in decreased pH due to the ubiquitous presence of carbonic anhydrase (CA) which converts CO₂ into bicarbonate (HCO₃), which in turn activates sAC.

Figure 2. sAC is found in various neuronal compartments

sAC localization and activity has been demonstrated in various neuronal compartments including the nucleus, axon, growth cone and cell body.

Figure 3. sAC has been linked to various neurotrophic signaling events in the growth cone

cAMP production, and subsequent protein kinase A (PKA) activation, by tmACs such as that stimulated by PACAP, has been shown to be distinct from other neurotrophic signaling pathways. However, sAC-mediated production of cAMP has been shown to be important for the neurite outgrowth signaling via nerve growth factor (NGF). sAC also mediates neurite outgrowth and growth cone guidance mediated by netrin, and sAC function also increases the neuronal response to netrin binding to the deleted in colorectal cancer (DCC) receptor. Interestingly, both netrin and NGF cause localized influx of calcium, which also activates sAC.

Figure 4. Electrical activity leads to activation of sAC

Electrical activity in the axon leads to influx, and intracellular release, of calcium which then directly activates sAC. This leads to increases in intracellular cAMP, which activates PKA and promotes neurite outgrowth.

Figure 5. sAC function leads to transcriptional changes in the nucleus

Nuclear-associated sAC responds to intracellular cues such as calcium and bicarbonate and leads to activation of CREB, which leads to transcriptional changes that support sustained neurite outgrowth.