Summary model depicting the diversity of noncanonical class I PI3K signal transduction elements and the proposed integration of PtdIns(3,4,5)P₃-dependent signal transduction in the GnRH-selective stimulation of acute hormone release from goldfish gonadotropes and somatotropes. In the majority of excitable cell models tested, production of PtdIns(3,4,5)P₃ by activated class I PI3Ks results in the recruitment of the canonical effectors PDK1, Akt, and BTK. More specifically, results in goldfish have demonstrated that GnRH-stimulated LH and GH release responses involve the activation of PLC, PKCs, and Raf-MEK-ERK cascades as well as Ca²⁺-dependent signaling mechanisms. PDK1 directly phosphorylates the T-loop activation segment of conventional (cPKC), novel (nPKC), and atypical (aPKC) isozymes of PKC. PKC activation is known to activate the Raf-MEK-ERK cascade through either direct phosphorylation of Raf, or indirectly through the activation of the Ras superfamily guanine nucleotide exchange factor Ras guanyl nucleotide-releasing protein (RasGRP). BTK activity also directly regulates the signaling activity of several families of MAPKs: including ERK1/2, p38 MAPK, and JNK. In addition to these classical targets, PtdIns(3,4,5)P₃-sensitive PH domains are present in a wide variety of intracellular signaling proteins. Examples of important noncanonical class I PI3K signaling effectors are shown. The involvement of the Arf guanine nucleotide exchange factors (GEFs) GRP1 and ARNO in the control of basal and GnRH-stimulated hormone release are implicated. Alternatively, PtdIns(3,4,5)P₃ is also known to recruit the Rac-GEF PtdIns(3,4,5)P₃-dependent Rac exchanger protein 1 (P-Rex1) to control, in concert with Arfs, actin remodeling and activate the Raf-MEK-ERK subfamily of MAPKs. Acute stimulation of PtdIns(3,4,5)P₃ production has also been implicated in the rapid trafficking of l-type voltage-sensitive Ca²⁺ channels and the direct gating of some isoforms of transient receptor potential channels to enhance extracellular Ca²⁺ entry. Last, isoforms of PLCγ directly bind and are activated by PtdIns(3,4,5)P₃ at the plasma membrane, although catalytic activity is also tightly regulated by Src family tyrosine kinases (such as c-Src) and BTK. PLCγ activation results in the activation of diacylglycerol (DAG)-sensitive isoforms of PKC, as well as stimulates intracellular Ca²⁺ release from inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃]-gated (IP₃R-containing) Ca²⁺ stores. Overall, these noncanonical mechanisms for the control of PtdIns(3,4,5)P₃-dependent signaling could result in the coordinate control of actin cytoskeleton dynamics and alter intracellular Ca²⁺ concentrations ([Ca²⁺]_i) to facilitate basal and agonist-stimulated hormone release responses. In fact, the recruitment of noncanonical effectors may help displace constitutively active PtdIns(3,4,5)P₃-sensitive effectors such as PDK1 or Akt to alleviate negative regulatory actions on exocytic vesicle docking or fusion events. In particular, Akt activation has been shown to phosphorylate and inactivate specific IP₃R subtypes to decrease [Ca²⁺]_i and, in many cell systems, Akt also directly attenuates Raf-dependent activation of MEK-ERK signaling. Relieving the inhibitory actions of Akt could significantly modulate basal, as well as agonist-stimulated, hormone release responses. PtdIns(3,4,5)P₃-dependent signaling has the potential to interact with many important transduction elements that are known to be activated downstream of GnRHRs in goldfish gonadotropes and somatotropes.