Adenylyl cyclase

Adenylyl cyclase

The Adenylyl cyclase is a 12 transmembrane glycoprotein that catalyzes the synthesis of cAMP from ATP with the help of cofactor Mg 2+ or Mn 2+.

Structure of the enzyme:

In vertebrates the enzyme usually contains about 1100 amino acid residues.

The membrane bound enzyme contains:

  • Two similar catalytic domains (on the cytosolic face of the membrane)
  • Two integral membrane domains (each of which is thought to contain six transmembrane helices).

Types of adenylyl cyclase

  • There are at least six types of this form of adenylyl cyclase in mammals (type I- type VI).
  • All of them are stimulated by Gs, but type I (found mainly in the brain) is also stimulated by complexes of Ca2+ bound to the Ca2+binding protein calmodulin.
Figure 1: Schematic diagram of mammalian adenylyl cyclase enzyme

Hormone induced activation and inhibition of adenylyl cyclase in adipose cells

  •  Ligand binding to Gs coupled receptors causes activation of adenylyl cyclase.
  • Ligand binding to Gi coupled receptors causes inhibition of the adenylyl cyclase enzyme.
Figure 2: Hormone induced activation and inhibition of adenylyl cyclase in adipose cells.

Table 1: Examples of hormones that stimulate and inhibit adenylyl cyclase

Adenylate Cyclase regulated by Gs and Gi type of Gα subunit of heterotrimeric G protein

  • The adenylate cyclase pathway regulated by both stimulatory and inhibitory subunits of G protein (Gs and Gi respectively).

In case of stimulatory subunit (Gs):

  • Gα have intrinsic GTPase activity, which is used to hydrolyze bound GTP to GDP and Pi.
  • This hydrolysis reaction is slow (requiring from second to minutes).
  • Thus the GTP form of Gα is able to activate downstream components of signal transduction pathway before GTP hydrolysis that deactivates the subunit.
  • After GTP hydrolysis and release of Pi, the GDP bound form of Gα then reassociates with Gβγ to reform the inactive heterotrimeric protein.

Gβγ can also directly participate in signal transduction by activation of wide variety of signaling proteins.

It includes the following:  Several isoforms of AC, certain Na+, K+ and Ca2+-specific ion channels, various protein tyrosine kinases and phospholipase C- β.

Gβγ thereby provides an important source of cross talk between signaling systems.

  • “Several types of ligand–GPCR complexes may activate the same G protein.
  • Example: In liver cells in response to the binding of the corresponding hormones to glucagon receptors and to β-adrenergic receptors.
  • In such cases, the amount of cAMP produced is the sum of that induced by the individual hormones.”

In case of inhibitory type of Gα subunit (Gi):

  •  Some ligand – GPCR complexes inhibit rather than activating Adenylyl cyclase.
  • Example: α2-adrenergic receptor and receptors for somatostatin and opioids.
  • The inhibitory effect is mediated by “inhibitory” G protein (Gi)
  • On binding to its corresponding ligand–GPCR complex, its Giα subunit exchanges bound GDP for GTP and dissociates from G protein heterodimer.

 

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