User:Dean Williams/Sandbox 1180

Introduction

Glucagon is released from pancreatic α-cells when blood glucose levels fall after a period of fasting or several hours following intake of dietary carbohydrates. Once the peptide hormone is released, it binds to GCGR which is a 485 amino acid protein found in the liver, kidney, intestinal smooth muscle, brain, and adipose tissue. ^[6] Upon binding, signaling is initiated to heterotrimeric G-proteins containing Gαs. ^[7] Additionally, GCGR can regulate additional signal pathways including G-proteins of the Gαi family through the adoption of differing receptor conformations. ^[8]

Comparisons to other G proteins

The class B GPCR GCGR is different from other Class A GPCRs in several ways. The first is that GCGR has a protrusion known as a 'stalk' which is a three helical turn elongation of the N-terminus that protrudes past the extracellular (EC) membrane. ((CAN WE INSERT LINK TO 2D PIC HERE??)) Secondly, the extracellular loop 1 (ECL1) is 3-4 times longer than comparable loops in class A GPCRs. Through mutagenesis studies, the stalk and ECL1 have been determined to affect ligand-receptor interaction. ^[9] ((INSERT 2D PIC OF STALK ACTIVE RESIDUES AND ECL1 ACTIVE RESIDUES)) Most notably, GCGR contains a prominent central splay which is solvent filled and accessible from the extracellular side. This central splay is notably absent from class A GPCRs and represents a tantalizing target for agonists/antagonists and is the focus of much current research into GCGR signal regulation. ^[3]

The Signal Peptide: Glucagon

Biological function of glucagon

Glucagon, a signaling ligand in the metabolic pathway, has three main biological functions.

Glucagon regulates the production of cholesterol, which is an energetically intensive process. When energy resources are low, downregulation of cholesterol production begins with glucagon binding to GCGR which stimulates the phosphorylation of HMG-CoA. Once the HMG-CoA has been phosphorylated, it is inactivated and cholesterol production is moderated to conserve energy.

Glucagon also takes part in fatty acid mobilization by affecting levels of adipose tissue in the organism. Activation of GCGR by glucagon initiates triacylglycerol breakdown and the phosphorylation of perilipin and lipases via cAMP. This allows the body to export the fatty acid to the liver and other crucial tissues for energy use and makes more glucose available for use in brain functioning. Through these processes, glucagon is able to increase glucose levels in the blood. Glucagon lowers the concentration of fructose 2,6-bisphosphate in the blood, which is an allosteric inhibitor of gluceogenesis. Glucagon also promotes the functioning of the enzyme fructose 1,6-bisphosphotase and activates phosphofructose kinase 1, which increases glucose levels via glycolysis.

^[10]

(Nelson & Cox, Principles of Biochemistry, 2008)

Glucagon Peptide Stability and Active Binding Sites

Essential, conserved residues of glucagon, as discovered through mutagenesis and photo cross-linking studies have been labeled and colored in red. ^[11]

Active binding domains/sites

Signaling pathways

GCGR signals generate downstream signals predominantly through the increase of intracellular cAMP, however there are other pathways being uncovered that are the result of GCGR adopting multiple, active conformations. Researchers are currently investigating how receptor activity-modifying proteins interact with the ligand and GCGR in which the signaling bias of the receptor is altered. ^[12]

Clinical relevance

Class B secretin-like receptors have gained relevance in therapeutics and drug targets. Maintaining information about the class B GPCRs conformational flexibility, allows for a better understanding of the receptor-ligand binding and its pharmaceutical relevance. The 7TM structure offers a direct connect between the extracellular and intracellular region, which offers a mechanism for signal transduction within the cell. GPCRs regulate cellular processes as required by the organs in which they are located. GPCR’s are used in the functioning of neuron synapses, ion transport regulation, homeostasis, cell division, and cell morphology. Mutations in the GPCR have been linked with retinitis pigmentosa, female infertility, nephrogenic diabetes insipidus, and familial exudative vitreoretinopathy. ^[13]

Future research direction

Research for Class A GPCRs is much more extensive than for its secretin, class B counterparts, although class B is proving to be a worthwhile to invest researching. The challenge of class B stabilization, expression, and molecular size , has made class B GPCRs particularly hard to assay. Biochemical research has increased in the class B specifications, because it has been realized that receptors can be modulated by more than the agonist and antagonists present in vivo. Leading research consists of a complex interwoven scheme of equilibria manipulation in multi-receptor conformations. ^[13]

Current drug targets

See “Landmark studies on the glucagon subfamily of GPCRs: from small molecule

		modulators to a crystal structure” good clinical references and small molecule 

target tables

Possible structural considerations for agonists

(our distance measurements and shape analysis images) Also see Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Relevance

Class B in Comparison to Class A

Figure Legend

Structural Similarities

Sequential Similarities

Current Drug Targets

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