## 5 Ca2+ and cAMP Signaling Are Intertwined  
The second messenger, Ca2+, is implicated in a variety of essential biological processes [45], making it critical to ensure correct concentration and localization. To maintain low Ca2+ concentrations in the cell, Ca2+ is pushed into the endoplasmic reticulum (ER) by SERCA pumps [46] or out of the cell by plasma membrane Ca2+ ATPases [47]. Gap junctions can mediate Ca2+ signaling between cells [48]. Channels located at the plasma membrane (PM), such as voltage-operated Ca2+ (VOCCs), receptor-operated Ca2+ channels (ROCCs), mechanically activated Ca2+ channels, transient receptor potential (TRP) ion channels, and store-operated Ca2+ channels (SOCCs) [49], also regulate the supply of Ca2+ from the extracellular space, and Ca2+ can be sequestered by the mitochondria [50]. Activation of phospholipase C (PLC) leads to the hydrolysis of phosphatidylinositol 4.5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (PIP3) and diacyl glycerol (DAG). PIP3 binds to the IP3 receptor (IP3R) on the ER to release Ca2+. G-proteins mediate this release primarily through phospholipase PLC\(\beta\)[51]. Numerous studies describe the complex and intertwined relationship of PKA, cAMP, and Ca2+ signaling [52]. For example, PKA can activate the ITR-1/IP3 receptor [53] and the ryanodine receptors (RYR), which mediate Ca2+ release from the ER in muscle and some non-muscle cell types [54; 55]. PKA can regulate Ca2+ release by activating plasma membrane channels, such as stretch-sensitive TRPV channels [56]. In mouse cardiomyocytes, G\(\alpha\) activation can stimulate Ca2+ release through exchange protein directly activated by cAMP (EPAC) and Rap1 by stimulating PLC\(\varepsilon\)[57; 58]. However, PKA does not always stimulate Ca2+ release; in rat brain cells, phosphorylation of IP3R by PKA-C decreases Ca2+ release [59]. PKA can lower cytosolic Ca2+ levels by increasing the activity of SERCA pumps, which pump Ca2+ back into the ER, by phosphorylating and dissociating phospholamban [60; 61]. PKA can inhibit PLC-\(\beta\)[62], which would result in decreased Ca2+ release. Additionally, adenylyl cyclases can be regulated by Ca2+ signaling [63], and IP3 receptors can be regulated by cAMP [64]. GPCRs regulate Ca2+ release through PKA in the _C. elegans_ intestine. KIN-1/PKA-C plays a role in the _C. elegans_ defecation cycle, which occurs rhythmically every 50 s [65]. The posterior, anterior, and enteric muscles contract sequentially to release waste [66]. GABAergic neurons (AVL and DVB) mediate the release of the neurotransmitter GABA, which prompts the release of gut contents by triggering muscle contractions [66; 67; 68; 69]. KIN-1/PKA-C functions in the GABAergic neurons to regulate this expulsion step, acting downstream of the GPCR, AEX-2, and neuropeptide NLP-40. Constitutively active PKA in GABAergic neurons was sufficient to partially bypass loss of AEX-2, and PKA modulates muscle contraction and promotes Ca2+ influx into the DVB neurons through the voltage-gated Ca2+ channels UNC-2 and EGL-19 [65]. KIN-1/PKA-C stimulates the release of Ca2+ in neurons through specific voltage-gated calcium channels to control rhythmic defecation cycles. Ca2+ and PKA signaling also coordinately regulate contractility in the _C. elegans_ spermatogenesis, a smooth muscle-like tissue in the reproductive system and the site of fertilization in _C. elegans_. Cell contractility in the spermatheca is dependent on actin and myosin and is regulated, in part, by Ca2+ signaling through the phospholipase PLC-1 [70], which mediates Ca2+ release from the endoplasmic reticulum. GSA-1/G\(\alpha_{\mathrm{s}}\), KIN-1/PKA-C, and KIN-2/PKA-R, regulate Ca2+ release and contractility in the _C. elegans_ spermatheca [44]. Without GSA-1/G\(\alpha_{\mathrm{s}}\) or KIN-1/PKA-C, Ca2+ is not released, and oocytes become trapped in the spermatheca.