A new mode of cAMP signalling: the adenylyl cyclase-IP3 receptor junction

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All cells separate themselves from their surroundings by wrapping themselves in an impermeable barrier, the plasma membrane, without which it would be impossible to maintain an intracellular composition distinct from that outside. But the plasma membrane is also a barrier to essential communication with the surroundings. Receptor proteins that span the plasma membrane overcome this problem by transmitting information across the barrier. These receptors selectively bind chemicals in the extracellular environment, change their shape, and the re-shaped intracellular part of the protein can then interact with intracellular proteins to initiate signalling cascades that lead to changes in cellular activity. Very commonly these protein-protein interactions at the plasma membrane lead to production of soluble intracellular chemicals, second messengers, that convey information to many different intracellular targets. The most remarkable feature of these signalling cascades is their economy: thousands of different extracellular stimuli, detected by a similar number of receptors converge to regulate the intracellular concentration of just a handful of second messengers. These then selectively regulate many hundreds of different cellular processes, including release of neurotransmitters, contraction, gene expression and cell growth and death. Defects within these signalling pathways are causes of common diseases and the proteins involved are among the most successful of drug targets. How can so few second messengers function to allow specific communication between so many extracellular stimuli and so many cellular responses? Three important features contribute to this versatility. First the second messengers, like Ca2+ and cAMP, are spatially organized within cells: an increase in Ca2+ concentration in one part of a cell can evoke very different effects to the same increase elsewhere. Second, interactions between signalling pathways allow complex information processing, such that a response may occur only when 2 pathways are simultaneously active. Third, signalling proteins, like the adenylyl cyclase that makes cAMP, come in different hues (subtypes) that differ in their regulation and interactions with additional proteins. Our understanding of the interplay between these features and their significance for reliable information processing is still in its infancy but there is real promise of new opportunities for therapeutic intervention. Our work is concerned with 2 ubiquitous signalling proteins: adenylyl cyclase (AC) and IP3 receptors (IP3R). The latter mediate most Ca2+ signals evoked by extracellular stimuli in animal cells. Our recent work suggests an entirely unexpected mode of communication between these 2 proteins, with cAMP passing directly from a specific subtype of AC (AC6) to a specific subtype of IP3R (IP3R2) to increase its sensitivity to IP3. We suggest that these signalling junctions, which may be a universal feature of second messenger pathways, allow robust signalling between the plasma membrane and intracellular proteins and autonomous processing of information within each junction. Our work seeks to identify the novel cAMP-binding site on the IP3R, to define the composition and structure of the AC6-IP3R junction, its regulation and its contribution to differential decoding of cAMP signals by the proteins that respond to it. Our work addresses a fundamental issue in cell biology, how information passes reliably from the plasma membrane to the cell interior, and it paves the way to identifying novel future drug targets.