Ca2+-sensitive adenylyl cyclases, key integrators of cellular signalling

Area of Science:

• Cellular Biology
• Molecular Signaling
• Biochemistry

Background:

• Second messenger signaling, initially recognized with cyclic AMP (cAMP), critically involves cytosolic calcium ([Ca2+]i) in numerous cellular events.
• Mammalian adenylyl cyclases (ACs) exhibit significant molecular and functional diversity, challenging the view of AC as a generic activity.
• Recent cloning of nine AC isoforms reveals complex regulation, with each isoform integrating diverse signaling pathways.

Purpose of the Study:

• To review the distinct regulatory properties and cellular distribution of calcium (Ca2+)-regulated adenylyl cyclase (AC) isoforms.
• To focus on the acute interactions between Ca2+ and cAMP and how physiological [Ca2+]i rises regulate AC activity in intact cells.
• To understand the temporal and spatial regulation of Ca2+- and cAMP-regulated pathways for specific cellular responses.

Main Methods:

• Review of existing literature on adenylyl cyclase isoforms, their regulation, and cellular distribution.
• Analysis of Ca2+ and protein kinase C (PKC) regulation across different AC families.
• Focus on physiological [Ca2+]i concentrations and their effects on AC activity in various tissues and cell lines.

Main Results:

• Nine mammalian AC isoforms, divided into four families, show distinct regulation by G-protein subunits, PKC, and Ca2+.
• Regulation mechanisms are often synergistic or conditional, suggesting ACs function as coincident detectors.
• Ca2+ regulation of ACs varies significantly, with stimulatory effects in the brain and inhibitory effects in peripheral tissues.

Conclusions:

• Ca2+ and cAMP act as 'synarchic' messengers, working in concert to regulate cellular activity.
• Ca2+-regulated AC isoforms exhibit characteristic distribution patterns, particularly in the brain.
• Understanding the interplay between Ca2+ and ACs is key to deciphering specific cellular responses to stimuli.