The β2-Adrenoceptor

The β2-adrenoceptor

  The β2-adrenoceptor is part of the GPCR family of membrane associated receptors. It is a natural receptor for the neurotransmitters adrenaline and noradrenaline, and is used to stimulate the 'fight or flight' mode in organisms. This mode is a survival instinct and a physiological reaction that occurs when the organism perceives a threat to itself, and allows the organism to gain temporary increased senses and strength to deal with the threat (Johnson, 2001)

   The associated G protein for this receptor is called Gs, and when it becomes activated it is used to activate the secondary messenger protein adenylate cyclase. Adenylate cyclase catalyses the conversion of ATP to cyclic AMP (cAMP). It is believed that these increased levels of cAMP can further activate protein kinase A (PKA), and can also inhibit calcium ion release from intracellular stores. PKA can in turn phosphorylate proteins involved in muscle activity (Rasmussen et al., 2011).

   The β2-adrenoreceptor allows this 'fight or flight' mode because the signal cascade it mediates leads to increased heart rate, pupil dilation, rapid energy mobilisation and diversion of blood to skeletal muscle. All of these are key to the ability to escape potential threats.

Structure of the β2-adrenoreceptor:
   Like all GPCRs, it is 7-transmembrane-domain protein, and its associated G protein (Gs) is made of α,β and γ subunits. The receptor is made up of 413 amino acids. There are 3 classes of β-adrenoreceptors, but this web page will focus on the β2 variety, shown below. There is very little variation in the tertiary structure and folding of the protein between the different agonist-bound varieties as shown by a sequence alignment in Pymol, raising questions about substrate-binding specificity and the ability of some proteins to bind multiple chemically distinct substrates. (Rasmussen et al., 2011).

A Pymol-modelled alignment of three different structures of the  β2 adenoceptor: in green, with the high affinity BI167107 engineered agonist bound; in blue, with hydroxybenzyl isoproterenol bound; and in purple with epinephrine bound (PDB accession codes 4LDE, 4LDL, and 4LDO respectively).  The Nb6B9 antibody fragment can be seen at the bottom of the protein; it is the β-sheet rich folded section dangling below the transmembrane helices.

Mechanism of the β2-adrenoceptor :

   An agonist molecule will bind to the N terminal of the receptor on the extracellular side. A conformational change is caused within the receptor due to this binding, which causes the Gs protein at the C terminal end of the receptor to exchange its bound GDP for GTP on the α subunit. This causes dissociation of the Gα subunit from the Gβγ, which is covalently attached to the membrane via lipid tails. The Gβγ subunit is used to regulate calcium ion channels.

   The Gα subunit can now go on to activate adenylate cyclase, which converts ATP to cAMP. cAMP can now activate further proteins in order to trigger the correct response in the cell for the 'fight or flight' reaction, as shown below.The Gα subunit has an intrinsic GTPase activity which can hydrolyse GTP back to GDP, allowing the reassociation of the Gs subunits and thereby terminating the signalling process (Alberts, 2008).