Bladder　cancer,　the　second　most　common　genitourinary　malignancy,　severely　endangers　the　human　health.　Rising　evidence　suggests　that　metabotropic　glutamate　receptors　(mGluRs)　are　involve　in　tumor　progression.　In　this　study,　we　observed　that　metabotropic　glutamate　receptor　4　(mGluR4)　was　functionally　expressed　in　normal　and　cancerous　bladder　cells　and　its　expression　was　positively　correlated　with　high　bladder　cancer　grading.　We　further　confirmed　that　the　activation　of　mGluR4　by　VU0155041,　an　mGluR4-specific　agonist,　decreased　cyclic　adenosine　monophosphate　(cAMP)　concentration　and　cell　viability,　promoted　apoptosis　and　inhibited　proliferation　in　bladder　cancer　cells,　whereas　MSOP　(group　III　mGluR　antagonist)　or　mGluR4　knockdown　eliminated　the　effects　of　mGluR4　activity.　Western　blotting　revealed　the　decreased　cyclin　D1　expression,　increased　procaspase-8/9/3　cleavage,　and　unbalanced　Bcl-2/Bax　expression　in　bladder　cancer　cell　lines　after　mGluR4　activation,　and　likewise　MSOP　and　mGluR4　knockdown　abrogated　the　actions　of　mGluR4　activity.　In　vivo　study　showed　that　mGluR4　activation　significantly　inhibited　tumor　growth　of　bladder　cancer　via　suppressing　proliferation　and　promoting　apoptosis.　Furthermore,　upregulation　of　phosphatase　and　tensin　homolog　(PTEN)　and　inhibition　of　Akt　phosphorylation　were　also　observed　after　mGluR4　activation.　Similar　with　VU0155041,　the　Akt-specific　inhibitor　markedly　promoted　apoptosis　and　inhibited　proliferation.　Nevertheless,　the　PTEN-specific　inhibitor　significantly　abolished　the　mGluR4　activation-induced　cell　apoptosis　and　proliferative　inhibition　in　bladder　cancer　cell　lines.　These　results　indicate　that　mGluR4　can　regulate　the　switch　between　survival　and　death　via　the　cAMP/PTEN/AKT　signaling　pathway　in　bladder　cancer　cells.　Our　findings　suggest　that　mGluR4　has　diagnostic　and　prognostic　potential　for　bladder　cancer,　and　the　development　of　mGluR4　agonist　may　be　a　promising　strategy　for　bladder　cancer　treatment.