Distinct types of specificity in intracellular signaling. Panel I: Two first messengers, A and B, each initiate a separate, private, linear signaling pathway that proceeds with type I specificity via oligomolecular handshakes. A or B may also arise intracellularly and activate a pathway that is entirely intracellular. Panel II: A micromolecular first messenger, C, may originate outside or inside the cell. C is shown arising from mitochondria, but there may be other intracellular origins, including type I pathways. C diffuses to various locations in the cell and initiates several signaling pathways. Where C is bicarbonate and the next component of the pathway is bicarbonate-activated adenylyl cyclase, cAMP diffuses a short distance to the next mediator, such as protein kinase A. Panel III: Private pathways with an associated enzymatic source of ROI or RNI (jagged circle), mitochondria, other organelles, cytosolic enzymes, and/or extracellular sources furnish D, a diffusible, micromolecular mediator that reacts covalently with submolecular specificity to modulate the activity of diverse other pathways. Panels II and III illustrate ways in which information can be shared publicly via discontinuous pathways. ROI and RNI act like D. In some cases, ROI and RNI may also act like A or C, except that activation of the pathway begins with a covalent reaction. Photo credit: Thom Graves.